Veterans Affairs Medical Center, Denver
To clarify the signaling mechanisms responsible for abnormal gene regulation secondary to metabolic stress and the contribution to cancer and diabetic complications.
Diabetes is a leading cause of death and disability worldwide and a leading cause of blindness, end stage renal disease, non-traumatic amputation and cardiovascular disease. Interventions to optimize glucose control, blood pressure and lipids dramatically decrease microvascular and macrovascular events yet excess burden remains. For example, even with optimal risk factor reduction cardiovascular events and death is 3-5 folds higher in people with diabetes.
The goal of the research ongoing in our laboratory is to define novel strategies for reduction of cardiovascular disease in diabetes. Two threads of research from our group weave together to inform this question. The first is our observation that the transcription factor CREB, cAMP Response Element Binding Protein, is a crucial modulation of cellular homeostasis. CREB regulates cellular differentiation of neurons, beta cells, adipocytes and smooth muscle cells; it is also a potent survival factor and an upstream regulator of mitochondrial biogenesis. In diabetes and cardiovascular disease, CREB protein content is decreased in the vascular media and its regulation in aberrant in beta cells, neurons and cardiomyocytes . Loss of CREB content and function leads to decreased vascular target tissue resilience when exposed to stressor such as metabolic, oxidative or sheer stress.
This first research program set the stage for our central hypothesis that diabetes mediated CREB dysfunction l predisposes the diabetes disease progression and cardiovascular complications. The second line of research, in collaboration with Dr Regensteiner, revealed the diabetes mellitus (Type 1 DM, Type 2 DM youth and adult) leads to defects in functional exercise capacity. This manifests in a 20-30% decrease in maximal VO2 consumption and slowed oxygenation and heart rate kinetics at submaximal exercise. Our group has determined that the defects in exercise correlate with insulin resistance, endothelial dysfunction, decreased cardiac perfusion and diastolic dysfunction, slowed muscle perfusion kinetics, decreased muscle perfusion and slowed oxidative phosphorylation ().In the past few years we have begun to weave these two threads together to define the relationship between exercise , blood flow and signaling to CREB and endothelial nitric oxide synthase (eNOS) as regulators of vascular function, tissue perfusion, mitochondrial content and function and exercise capacity.
Students will work on a project that can be completed during the fellowship. Such a project could include assessment of a specific signaling cascade, i.e., assessment of mitochondrial function and signaling to mitochondrial biogenesis , fission and fusion as a modulator of homeostasis and phenotype. Additional projects may involve immunohistochemistry for angiogensis profiling or work with the clinical research tea. Techniques to be employed include transient transfection, cell culture, SDS-PAGE electrophoresis, immunohistochemistry and immunoblotting. Student will be educated on all aspects of lab safety and will be versed in the physiological relevance of each project to human disease.