The candidate is an endocrinologist with strong training in basic science, specifically in the field of lipidology and is committed to applying these methods to the study of fatty acid metabolism in pancreatic islets. The candidate's long-term-career goal is to be an independently funded physician scientist, integrating basic science research with that of clinical practice for the diagnosis and treatment of metabolic disease. The candidate's short-term career goals are to 1) expand technical skills in the latest molecular biology, cell biology, metabolomics, and integrated physiology techniques (including animal models), 2) develop strong hypothesis-driven research program with a continued focus on mechanisms of metabolism, and 3) develop writing skills, grantsmanship and the skills necessary to become competitive in future independent funding proposals. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. Our hypothesis is that enzymes that activate fatty acids to long-chain acyl-CoAs (LC-CoAs), namely long-chain acyl-CoA synthetases (ACSLs), in pancreatic ss-cells regulate specific pools of LC-CoAs that play a functional role in glucose- stimulated insulin secretion (GSIS) and overall pancreatic ss-cell function. In this proposal, the PI will test the specific hypothesis that a specific acyl-CoA synthetase generates LC-CoAs that are channeled towards a signaling pathway that enhances GSIS and that another specific acyl-CoA synthetase channels LC-CoAs towards other synthetic and energy producing pathways.
In Aim 1, the PI will selectively knockdown the expression and therefore function of long-chain acyl-CoA synthetase 4 (ACSL4) in mouse islets using adenoviral RNAi technology and examine the effect of the knockdown on GSIS and islet lipid mediated signaling.
In Aim 2, the PI will selectively knockdown the expression of long-chain acyl-CoA synthetase 5 (ACSL5) in mouse islets using adenoviral RNAi technology and examine the effect of the knockdown on islet lipid synthesis and ss-oxidation. The expected outcome of this proposal is an improved knowledge of the mechanisms by which fatty acids augment GSIS. To support the candidate's career development, he will pursue coursework in basic mass spectrometry, biostatistical analysis, and research ethics. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in lipid metabolism (Coleman) and pancreatic islet biology and metabolism (Newgard) will guide Dr. Klett's research and career development. The research environment will provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals.
180 million people worldwide have Diabetes mellitus, a chronic disease characterized by elevated blood glucose and an inability of the pancreas to secrete insulin. Despite current therapies Diabetes mellitus results in significant morbidity, including heart attack, stroke, eye disease, kidney disease, and limb loss. The goal of this research and subsequent research is to determine the mechanisms by which fatty acids enhance insulin secretion that could lead to new strategies for the treatment of diabetes.
|Alves-Bezerra, Michele; Klett, Eric L; De Paula, Iron F et al. (2016) Long-chain acyl-CoA synthetase 2 knockdown leads to decreased fatty acid oxidation in fat body and reduced reproductive capacity in the insect Rhodnius prolixus. Biochim Biophys Acta 1861:650-62|
|Cooper, Daniel E; Grevengoed, Trisha J; Klett, Eric L et al. (2015) Glycerol-3-phosphate Acyltransferase Isoform-4 (GPAT4) Limits Oxidation of Exogenous Fatty Acids in Brown Adipocytes. J Biol Chem 290:15112-20|
|Cooper, Daniel E; Young, Pamela A; Klett, Eric L et al. (2015) Physiological Consequences of Compartmentalized Acyl-CoA Metabolism. J Biol Chem 290:20023-31|
|Zhang, Chongben; Cooper, Daniel E; Grevengoed, Trisha J et al. (2014) Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor. Am J Physiol Endocrinol Metab 307:E305-15|
|Grevengoed, Trisha J; Klett, Eric L; Coleman, Rosalind A (2014) Acyl-CoA metabolism and partitioning. Annu Rev Nutr 34:1-30|
|Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A (2013) Lipid signals and insulin resistance. Clin Lipidol 8:659-667|
|Klett, Eric L; Chen, Shufen; Edin, Matthew L et al. (2013) Diminished acyl-CoA synthetase isoform 4 activity in INS 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion. J Biol Chem 288:21618-29|