Dates of Funding: 2023-2025
I am a Postdoctoral Fellow in the Division of Endocrinology, Metabolism and Diabetes at the University of Colorado Anschutz Medical Campus. My research interest is to test and optimize physical activity and sedentary behavior interventions in adults at risk for chronic diseases. Reductions in postprandial glucose responses following active breaks to sitting are more pronounced in females than males over the short-term (<3 days). However, gaps in knowledge remain, including the mechanisms underpinning sex differences in glycemia responses and whether greater benefits are sustained over time. For my Colorado NORC pilot award, I propose to compare the 1-month effects of breaking up prolonged sitting on postprandial glucose responses, and skeletal muscle mitochondrial function and molecular pathways involved in glucose regulation in female versus male adults with prediabetes. Because hyperglycemia is a risk factor for type 2 diabetes and associated cardiovascular complications, determining those mechanisms may provide robust data to promote active breaks to sitting and better tailor physical activity prescription for the prevention of type 2 diabetes and cardiovascular diseases, particularly in females who are more vulnerable to these diseases.

Dates of Funding: 2023-2025
There is an ongoing obesity pandemic. Currently affecting close to half of all adults in the U.S., obesity is an independent driver of a number of chronic diseases including type II diabetes, non-alcoholic fatty liver disease and heart failure. In obesity, the large fat stores undergo lipolysis, releasing excess fats into the blood stream, a condition known as dyslipidemia. Dyslipidemia subsequently causes deposition of fat in peripheral organs, such as the heart and liver, contributing to their functional decline.

I have identified a new reversible post-translational modification on the enzyme hormone sensitive lipase (HSL), the rate-limiting enzyme regulating lipolysis. This post-translational modification inhibits HSL and lipolysis in fat cells. Following extensive cellular and molecular based research characterizing this new molecular pathway to block lipolysis, we have created a knock-in mouse with HSL that is resistant to this inhibitory modification. My NORC Pilot award will allow us to fully phenotype and characterize the brand-new mouse model at baseline and in the context of obesity. We predict this mouse will be dyslipidemia at baseline and will have worsened liver and heart function when fed a high fat diet.

Targeting this new pathway to block lipolysis in fat cells could mitigate the detrimental effects of obesity in peripheral organs, such as the heart, and prolong the healthy lifespan for obese individuals.

I am a senior postdoctoral fellow in the Division of Cardiology. Since arriving in Colorado in 2020, I have received additional funding from the American Heart Association and the Colorado Clinical and Translational Sciences Institute (CCTSI) to support myself and my research. Working together with the outstanding NORC faculty and core facilities has greatly enhanced and accelerated my work in understanding the pathological interaction between fat, the heart and other organs in obesity and metabolic disease.

Dates of Funding: 2023-2025
I am currently a postdoctoral fellow in the department of medicine, division of endocrinology, metabolism, and diabetes. I am currently funded by a NIH F32 and aspire to be an independent nutrient sensing scientist. My graduate training from James Madison University and Auburn University focused on nutrient supplementation strategies during and after exercise. To further understand how nutrients are sensed to promote cellular responses, I pursued my first postdoctoral fellowship at Penn State College of Medicine. I investigated how the stress-response protein family known as Sestrins affect how glucose contributes to cellular growth. Results from these studies suggested a strong role for Sestrins in regulating metabolism.

Dysfunction of skeletal muscle metabolism underpins many disease states including Diabetes Mellitus. Correcting dysfunctional skeletal muscle metabolism has proven to improve disease prognosis. Sestrin1-3 are a family of stress-responsive proteins that have been shown to directly affect the activation status of adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin in complex 1 (mTORC1) to maintain bioenergetic homeostasis. AMPK and mTORC1 are master regulators of bioenergetics such that their activation status is dysfunctional in many disease states. Given that Sestrins affect the activation status of both AMPK and mTORC1, Sestrins have been promising therapeutic targets to improve disease prognosis. Sestrin1/2 have been most studied; however, Sestrin3 is suggested to be the most impactful for metabolic regulation. Canonically, Sestrins have been thought to directly affect AMPK and mTORC1 activation to regulate metabolic processes; however, preliminary data suggests AMPK and mTORC1 activation is an indirect consequence of Sestrin-regulated glycolytic enzyme activity. Using translational models, cellular and molecular techniques, and stable isotope tracing, the precise function of Sestrin3-regulation on metabolism will be unveiled. Moreover, the proposed experiments will provide excellent training and a pathway to independence. It is anticipated that these findings can be leveraged to identify unique pharmacological targets and promote an area of research that is ripe for future investigation.

Dates of Funding: 2023-2025
Spanish-speaking adults are less likely to meet physical activity (PA) recommendations and have higher rates of overweight/obesity compared to English-speaking adults. Thus, there is an urgent need for culturally adapted lifestyle programs that target improved PA adherence among Spanish-speakers. The overall objective is to translate and culturally adapt an existing PA support program called Move, to create Movamonos (translates to “Let’s move”) by engaging Spanish-speaking co-designers (Aim 1) and then pilot test Movamonos in a single-arm field trial (Aim 2). Consistent with Designing for Dissemination and Sustainability (D4DS) and Equity methods, two frameworks will be integrated to guide the approach: 1) the Multiphase Optimization Strategy (MOST), and 2) the Practical Robust Implementation and Sustainability Model (PRISM). Dr. Ostendorf’s long-term goal is to equitably prevent and treat obesity, by designing and disseminating theory-based, optimized lifestyle interventions that promote sustained behavior change. With guidance from her mentors, she will develop expertise in conducting rigorous clinical trials, community-engaged research, human-centered design testing, and D4DS methods. Her experience, complemented by her mentoring team and expert bilingual research team will ensure success. Completion of this project will generate critical preliminary data to support a competitive R01 to evaluate the effectiveness of Movamanos in a fully powered trial.

Dates of Funding: 2022-2024
I am a Postdoctoral Fellow in the Department of Pediatrics, Section of Developmental Biology at CU-AMC. My research sits at the complex intersection of nutrition, neuroscience, and developmental biology. During pregnancy and early postnatal life, malnutrition can impair brain development, resulting in irreversible cognitive and psychiatric conditions. There is no question that adequate nutrition is vital for brain growth and maturation, but for many nutrients it remains unclear how deficiency alters neurodevelopmental programming at the cellular and molecular level. My NORC pilot project uses a zebrafish model to investigate the cellular consequences of omega-3 polyunsaturated fatty acid (omega-3 PUFA) deficiency during brain development. Omega-3 PUFA-deficient animals exhibit impaired immune responses by microglia, the brain’s resident macrophages. Microglia also regulate the formation and elimination of myelin, which insulates axons and increases the speed of nerve impulses. However, it is not known whether omega-3 PUFA deficiency culminates in the aberrant regulation of myelination. I will test this hypothesis by assessing whether omega-3 PUFA deficiency alters the microglial transcriptome (Aim 1), myelin maturation and morphology (Aim 2), and the dynamic microglia-myelin interactions in vivo (Aim 3). This work could provide insight into nutritional strategies for optimizing infant health and preventing neurodevelopmental disorders.

Dates of Funding: 2022-2024
I am currently a Post-Doctoral Fellow at the University of Colorado, Anschutz Medical Campus in the Division of Renal Disease and Hypertension. My long-term career goal is to become an independent research scientist with a focus on the interaction of lifestyle behaviors and health outcomes in individuals with kidney disease. I am supported by an NIDDK F32 fellowship, which focuses on patients with autosomal dominant polycystic kidney disease (ADPKD).  ADPKD is the most commonly inherited progressive kidney disease. Overweight and obese phenotypes have been associated with disease progression in early-stage ADPKD. Daily caloric restriction (DCR, 34% restriction per day from baseline weight maintenance requirements) may aid in weight loss and ultimately slow ADPKD disease progression. Weight loss via DCR may cause alterations in kidney oxidative metabolism and insulin sensitivity that can affect ADPKD disease progression. For my NORC pilot award, I will assess kidney oxidative metabolism and insulin sensitivity by leveraging an ongoing R01-funded trial (NCT04907799) in DCR vs. control groups at baseline (BSL) and 2 years. I will also utilize the clinical outcome measures performed in the parent trial to address the subsequent novel aims: Aim 1: Compare kidney oxidative metabolism and insulin sensitivity at BSL and 2 years in adults with ADPKD. Aim 2: Define the relations among changes in kidney oxidative metabolism, insulin sensitivity, total kidney volume, and weight over 2 years. Currently, it is unknown if weight loss via DCR modifies renal energy expenditure and substrate utilization. Collectively, this award will provide an opportunity to collect novel preliminary data and training for a future career development grant.

Dates of Funding: 2022-2024
I am a Post-doctoral Fellow in the Department of Pediatrics, Section of Nutrition at the University of Colorado – Anschutz Medical Center, supported by the Ruth L. Kirschstein National Research Service Award T32 Research Fellowship in Nutrition at the University of Colorado – Anschutz Medical Campus (CU – Anschutz). My research interest is in understanding the interactions of nutrition, maternal intrauterine exposures, and epigenetics on obesity risk in childhood. My long-term career goal is to establish myself as an independent physician scientist critically assessing the most optimal nutritional strategies for children at high risk of obesity and associated co-morbidities in the context of their interaction with genetic predisposition, susceptibility conferred via intrauterine exposures, and their effects on infant and child growth.  My interests lie in understanding the how the totality of these exposures and potential predictors can be moderated by evidence based nutritional interventions established earlier and sustained throughout the life course. 

Differences in childhood obesity risk may appear in infancy, suggesting that factors driving obesity begin operating very early in life. Neural, metabolic, and hormonal networks regulating energy balance are established in utero and are likely influenced by maternal exposures, including nutrition. Human studies have shown that such networks may be determined by epigenetic modifications, of which DNA methylation is the most well studied to date. Studies also indicate that maternal one carbon (1C) nutrient intake, such as that of folate and choline, peri-conceptionally and during pregnancy can influence both offspring adiposity and DNA methylation. Few studies, however, have aimed to evaluate the mediation of adiposity risk by DNA methylation in relation to its association with maternal 1C nutrient concentrations.  Differential DNA methylation, influenced by maternal 1C nutrient status, may serve as a marker at birth that predicts risk of adiposity, informing the need for additional clinical monitoring or alternative nutritional recommendations to prevent exacerbated growth.

For my NORC pilot award I propose to determine whether intrauterine exposure to maternal concentrations of folate and choline through 27 weeks gestation influences offspring adiposity and is mediated by DNA methylation identified at birth by leveraging data obtained from the Healthy Start Study (R01 DK076648, PI: Dabelea) an ongoing a large, multi-ethnic, prebirth cohort that has collected DNA methylation at birth in ~600 infants and longitudinal adiposity measures at birth, 5 months, and 5 years of age in the offspring.  More specifically, in this population of mother-infant dyads in which maternal intake of these two 1-carbon nutrient precursors is outside of recommended intake ranges during pregnancy, I aim to 1) precisely elucidate the effect of excessive folate status and inadequate choline status, based on maternal serum concentrations, on infant and child adiposity outcomes, and 2) examine mediation by DNA methylation in offspring cord blood.  Our results will contribute to knowledge and may clarify rising concerns regarding “population wide excess folate status” especially in pregnant women due to dose exposure and the potential for long term adverse effects on offspring health. This investigation will also indicate whether such status has any potential compensatory effect on offspring anthropometric outcomes or DNA methylation in the context of low choline concentrations amongst the population of maternal-infant dyads studied.  Additionally, the NORC award will facilitate my career goals of obtaining a future career development grant and establishing independently funded research.

Dates of funding: 2021-2023
Pediatric nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent obesity-related co-morbidity in youth. While experimental studies support associations of excess added sugar (AS) and sugary beverage (SB) intakes with NAFLD, findings from observational studies have been inconsistent, in-part due to measurement error associated with self-reported dietary assessment methods. The blood carbon isotope ratio (CIR) has shown promise as an objective biomarker of AS intake in the U.S., and may be a solution to limit this error, but few studies have tested it in pediatric populations. This proposal will address this gap by measuring serum CIR in three prospective pediatric studies (one controlled feeding intervention and two longitudinal cohort studies) and examining correlations with self-reported AS and SB intake in each study (Aim 1). We will also assess whether regression calibration of self-reported AS and SB intakes with serum CIR alters associations with hepatic fat (Aim 2) and whether the PNPLA3 rs738409 risk allele, a strong genetic risk factor for NAFLD, modifies sugar-hepatic fat associations (Aim 3). This proposal will establish feasibility in using serum CIR as a biomarker of AS and SB intake in youth and facilitate the applicant’s career goal of establishing an independently funded research program.

Dates of funding: 2021-2023
My clinical and research interests are in fetal and neonatal growth and nutrition. Intrauterine growth restriction (IUGR) is a common complication of pregnancy. Individuals with IUGR are not only at increased risk for morbidity and mortality in the perinatal period but are also at increased risk of developing metabolic diseases, such as type 2 diabetes, in adulthood. My long term research goals are to understand the factors, such as hormones and nutrients, that regulate fetal growth and to understand how the fetus adapts to abnormal nutrient availability. This knowledge is essential in order to develop strategies to mitigate abnormal fetal growth patterns and improve lifelong metabolic health. My NORC pilot project aims to understand how insulin-like growth factor 1 (IGF-1) and insulin, which are two critical fetal growth hormones that are known to be low in the IUGR fetus, work together to coordinate fetal nutrient availability to support fetal growth and protein accretion.

Dates of funding: 2021-2023
Loss of ovarian function greatly increases the risk of non-alcoholic fatty liver (NAFLD) in humans and rodents, and therapies available to treat this disorder are limited. In addition to other mechanisms that have been described, it’s likely that changes in adipose tissue in the postmenopausal state also contribute to NAFLD. Specifically, menopause and ovariectomy (OVX) favor the accumulation of pro-inflammatory bone marrow-derived adipocytes (BMDA) that may change the cellular composition of abdominal fat by enriching it with adipocytes that export harmful factors to the liver, and mechanisms that modulate BMDA infiltration are poorly understood. I hypothesize that limited calorie diets can restrict abdominal BMDA infiltration to improve NAFLD in rodents that undergo OVX, and I also propose that BMDA play a substantial direct role in mediating OVX-induced NAFLD development. To test this, 1) I will use weight maintenance and caloric restriction diets in mice that undergo OVX to determine if this strategy reduces BMDA infiltration and limits NAFLD progression, and 2) I will use genetic ablation of BMDA in OVX mice to test their direct contribution to NAFLD. Data obtained from these aims will provide novel insight into OVX-induced NAFLD and provide new therapeutic targets to treat this disorder.

Dates of funding: 2021-2023
I am currently a Research Instructor at the University of Colorado, Anschutz Medical Campus in the Department of Pediatrics, Nutrition Section. My long-term goal is to become an independent, NIH-funded investigator with a basic science research program focused on the role of thyroid hormones and their metabolites in regulating metabolism. Currently, I hold a KL2 Mentored Career Development Award through the Colorado Clinical and Translational Sciences Institute (CCTSI), where I am investigating the role of 3,3`-T2,  a thyroid hormone metabolite, in the cardiac recovery after myocardial infarction. I am also a recipient of L’Oréal USA’s 2020 For Women in Science (FWIS) Fellowship. My FWIS proposal assesses whether 3,3'-T2, in animal models with late-stage type 2 diabetes, induces proliferation of β-cell. Thus, my NORC pilot project supports my overall career goals as it seeks to deeply investigate the role of thyroid hormones and their metabolites’ on β-cell function. With this NORC pilot award, I aim to generate enough preliminary data to apply for NIH-R-level funding.

Dates of Funding: 2021-2023
I am a Senior Instructor in the Division of Endocrinology, Metabolism, and Diabetes and the Director of the NORC Lipidomics Core Laboratory at CU-AMC. The overall objective of my research is to expand our knowledge of lipid-induced insulin resistance and reveal potential novel lipid targets to modify muscle insulin sensitivity. My NORC pilot project focuses on the role of oxidized lipids in insulin resistance. The first goal of this proposal is to explore the role of oxidized lipids in the accumulation of sarcolemmal ceramides and insulin resistance in skeletal muscle. The second goal is to quantify oxidized lipid levels in plasma of endurance trained athletes, sedentary lean controls, and individuals with obesity and/or T2D by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We anticipate that these outcomes will provide clinical significance by identifying signaling pathways and mechanisms of accumulation of localized ceramides which can ultimately be targeted for the prevention and treatment of T2D.

Dates of funding: 2020-2022
I am currently an Assistant Professor at the University of Colorado-Anschutz Medical Campus (CU AMC) in the Division of Endocrinology, Metabolism, and Diabetes. I hold an NIH Career Development Award (K01 HL145023) investigating the extent to which patterns and timing of behaviors (physical activity, food intake, and sleep) influence body weight regulation. To date, my career has focused on identifying and improving strategies to treat and prevent overweight and obesity by linking behavioral and bioenergetic outcomes. My NORC pilot project aligns with my career focus as it seeks to examine the effects of exercise timing on weight loss and components of energy balance (energy expenditure and energy intake). This pilot study stems from our prior findings that morning and evening exercise result in different amounts of weight loss. We hope that this preliminary work will lead to future clinical and mechanistic studies on how the timing of exercise affects energy intake, energy expenditure, sleep, and ultimately body weight regulation.

Dates of funding: 2020-2022
I am an Assistant Professor at the University of Colorado Anschutz Medical Campus in the Division of Endocrinology, Metabolism, and Diabetes and a VA research scientist at the Rocky Mountain Regional VA Medical Center. The objective of my research is to better understand the diabetes burden in premenopausal women through the investigation of the cycle between type 2 diabetes and estrogen signaling. The primary themes of my research program are 1) to determine the interaction of diabetes and estrogen signaling on skeletal muscle mitochondria and 2) to elucidate the mechanisms by which endocrine therapies for breast cancer increase type 2 diabetes risk in cancer survivors. I am currently funded by a VA Career Development Award (CDA2) to investigate the interaction of diabetes and estrogen on metabolic flexibility and exercise tolerance in rats with hyperglycemia and hyperinsulinemia. My NORC pilot project aligns with my research program and provides added value to my CDA2 by exploring how the diabetic environment alters the gene expression signature associated with estrogen in skeletal muscle. The goal for the data generated with this NORC pilot award is to identify potential therapeutic targets in estrogen signaling that are disrupted in women with type 2 diabetes.

Dates of funding: 2020-2022
My specialized clinical training in pediatric gastroenterology and nutrition has cultivated my research passion to understand how nutrition contributes and affects clinical outcomes of pediatric patients with inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC).

Dates of funding: 2020-2022
My research interests lie in understanding to the contribution of endoplasmic reticulum (ER) health and unfolded protein response (UPR) in maintaining skeletal homeostasis in physiologic and pathological conditions. I have broad background and training in the domains of genetics, molecular biology, microscopy, skeletal biology and mechanistic studies in osteoporosis. I have extensive experience in generating and leveraging conditional mice knockouts relevant for studying mechanisms of bone loss in osteoblast lineage cells. During my post-doctoral training, I focused on understanding mechanisms that mediate bone loss with sex steroid deficiency and age and role of senescence as their mediator. Specifically, I examined the role of FoxO family of transcription factors and sex hormones and their receptors in skeleton in particularly in osteoblast progenitor cells. As a faculty at University of Arkansas Medical Sciences, I generated genetic mouse models to specifically address the role of UPR sensors in osteoblast lineage cells and bone health. I was funded by P20 NIGMS COBRE project as junior PI in Arkansas for one year, during which I developed expertise in various microscopy techniques for imaging bone including TEM to visualize ER of osteoblasts on tissue sections. In the context of this proposal, I will focus on the effects of high-fat diet on osteoblast progenitor cells and actions of the UPR sensor Perk in these cells as a contributor to obesity-related skeletal changes. The present application leverages my strong background in osteoblast biology to examine the role of fundamental cellular pathways to define the molecular basis of skeletal fragility in setting of obesity.

Dates of funding: 2020-2022
My long-term research interests are focused on understanding the molecular adaptations governing pathological myocardial remodeling, exercise intolerance, and the progression to heart failure in patients with congenital heart disease. The lab utilizes several unique tools to address the mechanisms of cardiac dysfunction including whole animal and cell culture-based models, as well as access to a meticulously preserved Pediatric Tissue and Blood Bank here at the University of Colorado Anschutz Medical Campus. My research objective is to improve our molecular understanding of heart failure in the pediatric congenital heart disease population with the goal of identifying efficacious therapies through basic science and clinical investigations and improving outcomes in this vulnerable group . I plan to accomplish these goals through several avenues including: 1) better understanding the molecular adaptations of pediatric heart failure, 2) identification of novel therapeutic targets, 3) animal and cell-based model development, 4) diagnostic and prognostic biomarker assessment, and 5) multi-omics data integration. My ultimate career goal is to be an independently funded full-time professor with expertise in pediatric cardiovascular disease, who runs a lab that contributes to the treatment and prevention of heart failure, and who participates in the training and mentoring of a diverse set of budding researchers.

Dates of Funding: 2018-2019
The overall goal of my research program is to understand the biological mechanisms by which exercise, sleep, and nocturnal metabolism influence risk for cardiovascular disease, diabetes, and obesity. Sleep has emerged as a key behavior that influences the risk of obesity and obesity related co-morbidities (e.g., diabetes, cardiovascular disease). During sleep, there are many dynamic changes in hormones and metabolites, such as secretion pulses in growth hormone and oscillations in glucose concentrations. Recent studies by my mentors have demonstrated that nocturnal free fatty acid concentrations and nocturnal fat oxidation are related to next day insulin sensitivity and risk for future weight gain. Further, disruptions in sleep quality, independent of sleep quantity, may cause many impairments in metabolism (e.g. insulin resistance, hyperglycemia) and increase the risk of weight gain. Collectively, these data indicate that nocturnal fat metabolism and sleep quality are related to clinically relevant health outcomes and represent an important and understudied area in the field of nutrition and obesity research. 

Individuals with obesity and metabolic syndrome (MetS) have an increased risk of chronic disease and frequently report sleep problems. Disrupted sleep quality may exacerbate the metabolic defects already present in individuals with MetS, thus, determining methods to positively impact sleep in this population is of great importance. Exercise has been a cornerstone of behavioral modifications to treat obesity for decades. There is evidence to suggest exercise improves sleep quality in healthy populations. However, the effect of exercise on sleep quality in individuals with underlying metabolic disease (e.g. obesity, MetS) is not known. Understanding whether exercise positively impacts sleep quality in this population is key in managing chronic disease risk. My current research is investigating how exercise impacts sleep quality and nocturnal metabolism in individuals with MetS.  I expect my findings will provide insight into how exercise and sleep interact to reduce chronic disease risk.

Dates of Funding: 2018-2019
My research to date has focused on the regulation of utero-placental function by environmental and endocrine factors and its role in the determination of fetal growth and offspring health. This interest began at the Centre for Trophoblast Research at the University of Cambridge. During my PhD I gained extensive experience of in vivo techniques in rodents, including experiments in pregnant animals and large-cohort, multigenerational studies investigating the feto-placental effects of glucocorticoids. In this period, I also obtained proficiency in gene and protein expression and morphometric analyses. I continued my research in this area during postdoctoral training at Cambridge, gaining additional experience of large animal metabolic studies and chronic catheterization techniques in sheep whilst also investigating more deeply the molecular actions of glucocorticoids in the placenta as part of a transcriptomic and bioinformatic project funded by a personal award from the British Society for Endocrinology. My rodent studies culminated in the publication of a series of papers on placental function during maternal stress which garnered interest in the scientific and UK national press. Subsequently, I took up a second postdoctoral position at University College London working upon a more translational project, aiming to develop a therapy for severe intrauterine growth restriction by targeting gene therapy to the uterine arteries in pregnant women. As part of this project, I expanded my expertise in cardiovascular physiology, overseeing protocols for measurement of blood pressure and cardiac morphology in guinea pigs. I moved to the University of Colorado in 2016 in order to gain additional experience in translational reproductive science, in particular capitalizing upon the enhanced opportunities for collaboration with clinical colleagues and access to human tissue available at Anschutz Medical Campus. As a result of this research, I have published 21 research papers (10 first author, including 2 based on my work in Colorado), 8 review articles and over 20 conference papers since 2010. The focus of my current research is the molecular mechanisms by which offspring cardiac dysfunction is programmed in utero in maternal obesity and I have recently reported that normalization of maternal adiponectin levels in obese pregnant mice prevented the development of diastolic dysfunction.  Thus, my research links maternal obesity and nutrition during pregnancy with the long term programming of metabolic disease in children.

Dates of funding: 2018-2019

Dates of funding: 2018-2019
Diabetes affects more than 20 million people in the United States, or roughly 1 of out 11 individuals and obesity-induced diabetes incidence is steadily increasing. Despite great efforts, there is unfortunately still no cure. The best treatments for the disease require constant and diligent patient management and even when managed appropriately, the disease can still lead to serious complications like heart disease, blindness, and amputation. We have long known that obesity is a great risk factor for diabetes, however, many of the disrupted genetic pathways that contribute to the disease are still unknown. My proposal seeks to identify novel molecules involved in the onset and/or progression of diabetes with the ultimate goal of discovering effective therapeutics for the many patients affected by diabetes. In particular, I am focusing on a novel class of molecules called long non-coding RNAs (lncRNAs), which were previously unknown to be important in biology, but contain properties that facilitate therapeutic targeting. In this study, I have identified a new lncRNA that becomes highly upregulated in the β cells of several obese-diabetic mouse models and islets from obese diabetic patients. We hypothesize that this lncRNA is important for the onset and/or progression of diabetes and we propose a set of studies to determine its specific role during disease development and assess whether targeted disruption of its expression can improve β cell function and patient outcomes.

Dates of funding: 2018-2019
While breastfeeding is known to improve neonatal and long-term health outcomes in humans, many mothers, especially those with obesity or insulin resistance, have difficulty initiating and/or maintaining sufficient milk production to sustain breastfeeding. Exclusive and extended lactation protects against subsequent metabolic impairments in these mothers, who are at increased risk of developing type 2 diabetes, and in their offspring, who are at elevated risk for prediabetes during youth. However, basic biological mechanisms and physiological processes regulating lactation initiation and adequate milk production remain poorly understood. The focus of this proposal is to evaluate insulin signaling in mammary epithelial cells in women with insulin resistance during pregnancy with regard to their lactation outcomes. The results from this study will lay a foundation upon which to develop rational interventions and/or therapeutic strategies to improve breastfeeding outcomes.

Dates of funding: 2018-2019
Role of fructose in early life predisposition to childhood obesity
Rates of obesity and its co-morbidities are increasing alarmingly throughout the world due to a complex mix of dietary, environmental, and behavioral factors.  Of great concern, 15% of 2-5 year-old children in the U.S. are now obese and more than one third (36,5%) of US adults are obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death. Significantly, emerging evidence indicates that the risk factors associated with obesity and other aspects of metabolic syndrome (MetS) may exert their influence prenatally. Hyper-caloric intake of fat and nutritive sweeteners, such as high-fructose corn syrup, plays perhaps the most crucial detrimental role in this epidemic. However, avoidance of dietary sugar has become increasingly challenging as it is frequently added to all types of food. Our group has focused on the fructose component of sugar in the pathogenesis of metabolic disease and we are actively involved in identifying modifiable biological factors contributing to sugar-induced MetS. Among these potential targets, we have identified the enzyme fructokinase, which catalyzes the first step in conversion of fructose into fat and calories, as a potential candidate to slow the progression of MetS induced by sugar. If the hypothesis tested in this proposal is correct, our findings will lead to new therapeutic approaches to combat the current epidemics of metabolic syndrome and obesity in kids. More specifically, our work will lead to the potential discovery and use of fructokinase inhibitors and fructokinase knockout derived probiotics to be used during pregnancy and lactation to significantly reduce the risk of developing metabolic syndrome during childhood.

Dates of funding: 2018-2019
Ovulatory dysfunction is responsible for 25% of cases of subfertility and is frequently present in women with excessive body weight. Specifically, a high-fat intake causes excessive storage of lipid in non-adipose tissue, including the ovary, which can affect its physiological function and result in reproductive dysfunction in women. Recommended daily intake of fat is 20-30% of total calories, but most American women consume a diet containing at least 35%. Therefore, it is important to consider the impact of elevated dietary fat in ovarian dysfunction, especially as diets promoting high fat intake are becoming very popular, some resulting in a significant weight loss. There is theoretically a considerable population of women impacted by HFD-induced reproductive dysfunction of which the burden and mechanistic causes of action are undetermined. One potential reason why HFD causes an abnormal ovulatory function includes changes in genes critical to normal ovarian function. Endothelin-2 (Edn2), which is crucial in ovulation, was the most significantly altered gene upon exposure to HFD in my previous studies, regardless of obesity. Endothelin-2 (ET-2) is a recently identified protein that is secreted by ovarian granulosa cells and plays a critical role in ovulation and corpus luteum formation.The mechanisms regulating Edn2 expression in the ovary are not clear and in some cases controversial. Therefore my current research focuses on investigating mechanisms behind abnormal Edn2 expression in HFD exposure. Our central hypothesis is that HFD leads to diminished ovarian estrogen receptor (ER) signaling, with subsequent Edn2 downregulation and impaired ovulation. The knowledge that will be gained from the proposed experiments is critical to understanding the mechanisms behind HFD-induced ovulatory dysfunction. This new knowledge will help me uncover some important clues in previously unexplained ovulatory dysfunction and subfertility and design potential treatment strategies in women in the future.

Dates of Funding: 2017-2019
The Impact of Insufficient Sleep on Peripheral Metabolic Tissues
Short nightly sleep duration and untreated sleep disorders are now recognized as risk factors for metabolic diseases with more than 35%of Americans sleeping less than the recommended 7 hours/night. Acute, experimental sleep restriction studies have demonstrated inadequate sleep alters glucose homeostasis, primarily by decreasing whole-body insulin sensitivity. However, the mechanisms responsible for the adverse effect of sleep restriction on insulin sensitivity are not known and understanding the effects of sleep restriction on other metabolic tissues is in its infancy. Our long-term goal is to demonstrate the importance of adequate sleep duration and to establish sleep as a third pillar of health—in addition to diet and exercise—in the maintenance of cellular, tissue and whole-body metabolic homeostasis. The overall objective for this project is to determine how insufficient sleep impairs insulin sensitivity in peripheral metabolic tissues biopsied from healthy young lean men and women after normal and insufficient sleep.

Dates of Funding: 2017-2019
Influence of Acute Exercise Modality on Hormonal and Behavioral Appetite Regulation and Energy Intake
Lifestyle interventions are often successful in promoting weight loss, but maintenance of weight loss  is often unsuccessful due to biological and behavioral adaptations that favor weight regain. The efficacy of exercise for weight loss and weight loss maintenance is often attributed to its effect on increasing energy expenditure, but exercise may assist in weight management by improving    appetite regulation and helping individuals control energy intake (EI). While promising, research is limited, findings are inconclusive, and mechanisms by which exercise influences appetite regulation remain unknown. Furthermore, most studies have focused on aerobic exercise (AEx), and the few involving resistance exercise (REx) have primarily studied normal weight adults. Therefore, it is unknown how different exercise modalities, and specifically REx, may uniquely influence appetite regulation and EI in overweight/obese (OW/OB) adults. The primary goal of the proposed study is to compare the acute effects of REx and AEx in OW/OB adults on appetite regulation and EI. To   achieve this goal, appetite ratings, appetite-related hormones, eating-related behaviors, and EI will   be compared following acute bouts of Rex, AEx, and a sedentary control condition. Results of this study will provide insight on how exercise modality deferentially influences acute appetite and EI.

Dates of funding 2017-2019
Impact of dietary nitrate supplementation via beetroot juice on skeletal muscle metabolic control and exercise tolerance in sickle cell anemia
Sickle Cell Disease results in severely compromised exercise capacity, and thus the quality of life, for those afflicted. This is due to both central cardiopulmonary and peripheral vascular factors which conspire to reduce maximal oxygen uptake (VO₂max) and instill premature fatigue during exercise. SCD results in high rates of hemolysis and the resulting release of free-hemoglobin (HB) rapidly scavenges nitric oxide (NO) resulting in impaired cardiovascular control. Our work focuses on the impact of Hb on skeletal muscle vascular and metabolic control as this is likely a primary mechanism of peripheral vasculopathy and exercise decrement in SCD.

Over the past decade, a plethora of investigations have demonstrated the robust efficacy of dietary nitrate supplementation in the treatment of many prevalent diseases related to loss of NO bioavailability; accordingly, it has been hailed as an “unrecognized nutrient.” Previous investigations in humans and animals have demonstrated that NO₃^–, when consumed, serves as a powerful controller of muscle O₂perfusion, presumably following its reduction to nitrite (NO₂^–) and NO in vivo. Collectively, these results strongly support the premise that dietary NO₃^– as a nutritional therapeutic will ameliorate Hb-mediated NO depletion for patients with SCD, and therefore evoke improved exercise tolerance and quality of life. Thus, this project is aimed at uncovering the mechanistic basis for skeletal muscle dysfunction in SCD and the therapeutic potential of dietary NO₃^– in preclinical models of this disease. Results from these investigations will directly impact the design of future clinical studies at the University of Colorado, Denver in the coming years.

Dates of funding: 2014-2017
In people with diabetes (DM), cardiovascular disease, (CVD) is a major cause of death; this is not alleviated by CVD management or standard treatments for DM. Vascular contractility and mitochondria dysfunction are not only associated with hyperglycemia, decreased antioxidant defense, and insulin resistance, but precede vascular inflammation, vascular stiffness, and smooth muscle cell (SMC) apoptosis. As we and others have shown that nitric oxide synthase (NOS) enzymes regulate contractility and mitochondrial function, targeting NOS recoupling is a potential strategy for novel vasculature therapeutics in DM. Sepiapterin, a NOS coupler, has been shown to restore NOS function both in vivo and in vitro. Our findings in vivo with sepiapterin supplementation include an unexpected beneficial effect on blood glucose. This compound also significantly normalized both vascular contractility and mitochondrial function. This proof-of-concept study provided a platform for the research of other potentially bioactive and multifactorial compounds, sourced from medicinal plants, as homeostasis regulators in the diabetic vasculature. To date, we have continued our in vivo and in vitro studies begun in our pilot award, and broadened our investigation of other in vivo function and cellular mechanisms of action. (-)-epicatechin (EPICAT), a compound found in food and known to modulate NOS activity is central to our current work, and we and others have shown that it restores vascular relaxation and modulates mitochondrial activity. Overall, our research continues to investigate whether disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism.

Dates of Funding to: 2016-2019
PTH and Calcium responses to Exercise in Older Adults (PACE Sr.)
Age-related increases in osteoporotic fracture are associated with a large healthcare burden. Weight-bearing exercise is recommended to prevent osteoporosis, but emerging evidence indicates exercise may not always result in osteogenic benefit. Preliminary work suggests calcium losses during exercise triggers increases in bone resorption and are attenuated by calcium supplementation. Therefore, the global aim is to investigate nutritional contributions to calcium homeostasis, including calcium needs during exercise. SA1 will determine if preventing serum ionized calcium (iCa) declines during exercise prevents increases in bone resorption. Participants will complete walking bouts under conditions of 1) intravenous calcium infusion (prevent iCa decline) and 2) volume-matched saline infusion. We hypothesize that exercise will stimulate resorption to stabilize iCa concentration more under the saline condition. Additionally, SA1 will measure calcium infusion amounts needed to prevent iCa declines. SA2 will determine how bisphosphonate medication impacts this relationship. Bisphosphonates diminish osteoclast activity, which is believed the be the cell primarily responsible for bone resorption during exercise. However, if bone resorption still increases during exercise, this would suggest that the osteocyte contributes to calcium homeostasis. To our knowledge, this will be the first study investigating osteocytic osteolysis in vivo in humans. Combined, these experiments will inform future supplementation trials to determine calcium recommendations. Long-term, this may lead to improved bone adaptations and reduced osteoporosis-related incidents.

Dates of funding: 2014-2018
My research focuses on women's health, obesity, weight loss, and disease prevention. Her main project during fellowship was the TEAM GDM (Taking Early Action for Mothers with Gestational Diabetes Mellitus) study, where she and a team of researchers at Brigham and Women's Hospital developed and tested Balance after Baby, a web-based lifestyle intervention program for women with recent gestational diabetes. She is currently developing a mobile health lifestyle intervention program called Fit After Baby for postpartum women at high risk for cardiometabolic disease.

Dates of funding: 2014-2017
In people with diabetes (DM), cardiovascular disease, (CVD) is a major cause of death; this is not alleviated by CVD management or standard treatments for DM. Vascular contractility and mitochondria dysfunction are not only associated with hyperglycemia, decreased antioxidant defense, and insulin resistance, but precede vascular inflammation, vascular stiffness, and smooth muscle cell (SMC) apoptosis. As we and others have shown that nitric oxide synthase (NOS) enzymes regulate contractility and mitochondrial function, targeting NOS recoupling is a potential strategy for novel vasculature therapeutics in DM. Sepiapterin, a NOS coupler, has been shown to restore NOS function both in vivo and in vitro. Our findings in vivo with sepiapterin supplementation include an unexpected beneficial effect on blood glucose. This compound also significantly normalized both vascular contractility and mitochondrial function. This proof-of-concept study provided a platform for the research of other potentially bioactive and multifactorial compounds, sourced from medicinal plants, as homeostasis regulators in the diabetic vasculature. To date, we have continued our in vivo and in vitro studies begun in our pilot award, and broadened our investigation of other in vivo function and cellular mechanisms of action. (-)-epicatechin (EPICAT), a compound found in food and known to modulate NOS activity is central to our current work, and we and others have shown that it restores vascular relaxation and modulates mitochondrial activity. Overall, our research continues to investigate whether disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism.