Narkar, Vihang A, PhD
Estrogen-related receptor gamma signaling in diabetic muscle angiopathy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Exercise\Regulation of Muscle Metabolism, Integrated Physiology, Integrated Physiology\Muscle, Metabolism, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transcriptional Regulation
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Maintenance of skeletal muscle blood supply is paramount for its health. For example, regular exercise increases blood vessels and flow in the muscle to meet the oxygen and nutrient demands of the trained muscle. Loss of blood vessels in muscles of diabetic patients results in wasting, pain and fatigue, increasing the likelihood of gangrene and limb amputation. Unfortunately, conventional biological factors (e.g. HIF) that typically restore blood supply to ischemic tissues are impaired by diabetes and are poor drug targets. Therefore, search for alternative factors to treat this condition is warranted. We recently discovered, using mouse genetic engineering, that a gene regulator named ERRgamma can promote muscle vascularization.
Our observation raises the promise that this factor may be important for vascular adaptation of the muscle in exercise, and also for preventing or treating muscle vascular damage in diabetes. In this project we will investigate the potential role of ERRgamma in increasing blood supply to the skeletal muscle during exercise, and in preventing vascular complications of diabetic muscle. Additionally, we will investigate the interaction between ERRgamma and HIF in regulating blood vessels.
Overall, our research will identify a regulatory protein that can enhance blood flow to the skeletal muscle in exercise and diabetes. ERRgamma belongs to a class of proteins that are excellent pharmaceutical targets. Therefore, our work has implications in developing a pharmaceutical treatment for diabetic muscle disease. Our findings may also be useful for advancing treatment of other complication of diabetes (e.g. stroke and cardiac myopathy).
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
Diabetic muscle angiopathy is a major complication of diabetes. This complication is linked to loss of blood vessels and flow to the skeletal muscles of the legs, resulting in muscle wasting and ultimately limb loss. Despite its prevalence in diabetic patients, there is no pharmaceutical treatment available for muscle angiopathy. This pre-clinical project is designed to investigate a gene regulatory pathway, named ERR-gamma, and its control of skeletal muscle blood flow at rest and during exercise as well as the role of ERR-gamma in promoting blood vessel growth and re-perfusion in diabetic muscles. Therefore, our work is a step towards understanding the regulation of skeletal muscle blood flow in diabetes, and towards advancing the treatment of diabetic muscle angiopathy, a condition with an unmet medicinal need.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Normal blood flow to the skeletal muscle is of paramount importance to its viability. Loss of blood vessels in chronic or uncontrolled diabetes often causes muscle loss, which in turn results in limb amputation. Through our research we will investigate how blood vessel growth and blood flow to the skeletal muscle is normally regulated at rest and during exercise, as well as in pre-clinical models of diabetes.
Upon successful completion, our investigation will facilitate future development of drugs for treating skeletal muscle ischemia in diabetic angiopathy. In addition, our finding will also be valuable to developing treatment for other vascular complications of diabetes such as myopathies, stroke and nephropathy.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Approximately 11.3% of the population over 20 years of age are diabetic in United States. This statistics further increases to over 26.9% in age group over 65 years. Even larger percent of the population go undiagnosed and are pre-diabetic. Diabetes is associated with multiple and severe vascular complications that dramatically increases the impact of the disease. This impact is personally felt with more than one of my family members affected by diabetes and/or its complications. While the pathogenesis of diabetes is extensively researched, the biochemical basis of the onset of vascular complications and the molecular strategies to prevent these complications are under-explored.
Therefore, in my capacity as a research scientist I am interested in understanding the molecular pathways involved in diabetic vascular complications, and there therapeutic targeting. This award from ADA will help me pre-clinically elucidate the role of a muscle angiogenesis pathway identified in my laboratory in not only vascular adaptations to exercise training, but also in mitigating diabetic muscle angiopathy - a major diabetic complication.
In what direction do you see the future of diabetes research going?
Molecular biology and high-throughput screening technologies (e.g. genomics, proteomics) along with pre-clincial models of metabolic physiology, diabetes and vascular complications will be increasing applied to facilitate discovery of biomolecular pathways involved in glucose, metabolic and cardiovascular homeostasis. These discoveries will help future therapeutic developments in diabetes and diabetes-related diseases.
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