Md. Shenuarin Bhuiyan, PhD, Assistant Professor of Pathology, has received an R01 grant from the National Institutes of Health. Dr. Bhuiyan’s new $1,825,000 5-year grant will fund his research project, “Sigmar1 in lipid metabolism.” Obesity, diabetes and heart diseases are characterized by metabolic dysfunction and affect one-third of adults in the United States. Dr. Bhuiyan’s proposal will investigate a novel function of protein named Sigma-1 receptor (Sigmar1) in regulating lipid metabolism in baseline and in response to diet-induced obesity. The goal of this application is to discover a novel lipid metabolism pathway regulated by Sigmar1 and identify a therapeutic target to prevent lipid abnormalities in obesity, which is expected to help reverse the impact of obesity on cardiovascular disease risk. Obesity is associated with ectopic deposition of lipid (steatosis) in different organs including the pancreas, kidneys, blood vessels, liver, skeletal muscle, and heart. The accumulation of excessive toxic lipid species alters cellular signaling, promotes mitochondrial dysfunction, and increases cellular death in these organs.
“We became interested in uncovering the molecular function of Sigmar1 proteins in metabolism as it was reported to be associated with lipid-containing micro-domains suggesting a potential role in the pathophysiology of metabolic diseases. We found that Sigmar1 is abundantly expressed in the heart, where fatty acid oxidation serves as the primary source of energy, approximately 70%,” said Dr. Bhuiyan. “Our preliminary data central to this proposal identifies tissue-intrinsic function of Sigmar1 as an essential regulator of lipid metabolism under the normal physiological condition and in response to diet induced obesity stress.”
To explain the molecular function of Sigmar1 under physiological and pathophysiological conditions, Dr. Bhuiyan’s laboratory recently generated a cardiac-specific Sigmar1 transgenic mouse for overexpression, and cardiac-specific Sigmar1 conditional knockout mouse models. The central hypothesis of the research project proposal is that Sigmar1-dependent activation of lipid metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling.
Dr. Bhuiyan’s research will aim to test this hypothesis by pursuing three specific aims:
- Aim 1 will determine a novel function for Sigmar1 in regulating lipid metabolism.
- Aim 2 will determine the role of Sigmar1 in metabolic stress in mouse model of diet-induced obesity.
- Aim 3 will determine the molecular mechanism of Sigmar1’s function in lipid metabolism through mitochondrial fatty acid uptake and oxidation.
Dr. Bhuiyan’s lab will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement, and define the molecular mechanisms of Sigmar1’s role in lipid metabolism. This proposed project will identify a novel therapeutic target to regulate mitochondrial fatty acid oxidation and discover a novel molecular mechanism of cellular protection in diet-induced obesity.