Role of acyl-CoA synthetases in mouse pancreatic ??-cell function

总结 候选人是一名内分泌学家，在基础科学方面受过良好的培训，特别是在脂质学领域 并致力于将这些方法应用于胰岛脂肪酸代谢的研究。的 候选人的长期职业目标是成为一名独立资助的医生科学家， 科学研究与临床实践相结合，用于代谢性疾病的诊断和治疗。的 候选人的短期职业目标是：1）扩展最新分子生物学，细胞 生物学、代谢组学和综合生理学技术（包括动物模型），2）发展强劲 假设驱动的研究计划，持续关注代谢机制，以及3）开发 写作技巧，语法和必要的技能，成为在未来的独立资金的竞争力 提案拟议的研究计划、职业发展活动、导师团队和机构 环境都非常适合帮助申请人实现这些目标。我们的假设是 将脂肪酸活化为长链酰基辅酶A（LC-CoA）的酶，即长链酰基辅酶A合成酶 （ACSL），在胰腺ss细胞中调节在葡萄糖代谢中起功能作用的LC-CoA的特定池。 刺激的胰岛素分泌（GSIS）和整体胰腺β细胞功能。在本提案中，PI将测试 特定酰基辅酶A合成酶产生LC-CoA的特定假设， 增强GSIS和另一种特异性酰基辅酶A合成酶通道LC-CoA的信号通路 转向其他合成和能源生产途径。在目标1中，PI将选择性地敲低 长链酰基辅酶A合成酶4（ACSL 4）在小鼠胰岛中的表达及其功能， 腺病毒RNAi技术，并检查敲低对GSIS和胰岛脂质介导的 发信号。在目标2中，PI将选择性地敲低长链酰基辅酶A合成酶5的表达。 使用腺病毒RNAi技术在小鼠胰岛中检测ACSL 5的表达，并检查敲低对胰岛的影响。 脂质合成和β-氧化。这一建议的预期成果是， 脂肪酸增加GSIS的机制。为了支持候选人的职业发展，他将 攻读基础质谱、生物统计分析和研究伦理学课程。营商友导 团队，其中包括国际公认的，独立资助的研究人员与脂质的专业知识 代谢（科尔曼）和胰岛生物学和代谢（纽加德）将指导Klett博士的研究 和职业发展。研究环境将提供一个富有成效的，合议，和协作 为实现上述研究和培训目标创造了良好的氛围。

SUMMARY 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.