The Role of Clec16a in the Pancreatic Islet

Clec16a 在胰岛中的作用

基本信息

批准号：
8242336
负责人：
Scott Soleimanpour
金额：
$ 15.51万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242336
关键词：
Affect Alleles Area Autophagocytosis Autophagosome Award Biogenesis Biological Assay Cell Line Cell Proliferation Cell physiology Cells Co-Immunoprecipitations Complex Confocal Microscopy Data Development Diabetes Mellitus Doctor of Medicine Doctor of Philosophy Drosophila genus Electron Microscopy Electron Transport Endosomes Environment Evaluation Faculty Family Future Genes Genetic Genomics Glucose Goals Growth Factor Homeobox Human Immune Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Label Lectin Ligand Binding Maintenance Mediating Medicine Mentors Mentorship Mission Mitochondria Mus Oxygen Consumption Pancreas Pathogenesis Pathway interactions Pennsylvania Physicians Physiologic pulse Population Presynaptic Terminals Production Proteins Regulation Research Research Training Resources Respiration Role Scientist Signal Pathway Signal Transduction Sirolimus Supervision Susceptibility Gene Testing Tracer Universities base blood glucose regulation career career development didactic education gene function glucose tolerance improved in vivo insulin secretion islet late endosome loss of function medical schools member mouse model novel professor receptor release of sequestered calcium ion into cytoplasm research study trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant: This proposal details the research and training plan for Scott Soleimanpour, M.D. to develop his academic career as a physician-scientist focused on the thorough understanding of factors which regulate pancreatic ¿-cell replication and survival, with the eventual goal of improving treatment of type 1 diabetes. The career development portion of the proposed K08 award includes an advanced didactic curriculum and formal research mentoring under the supervision of the primary mentor, Doris A. Stoffers, M.D., Ph.D., Associate Professor of Medicine at the University of Pennsylvania School of Medicine, and a multi-disciplinary mentorship committee. The University of Pennsylvania School of Medicine offers a research-rich environment with open access to a wide assortment of expert faculty and resources that will be beneficial in the scientific and professional development of Dr. Soleimanpour. The research proposed in this K08 application will focus on the ¿-cell specific role of Clec16a (C-lectin domain family 16, member A), a type 1 diabetes susceptibility gene and novel target of the essential ¿-cell transcription factor Pdx1. The Drosophila orthologue of Clec16a, Ema, is an endosomal protein vital to endosomal maturation through direct interaction with the Vps-C HOPS complex, which regulates key transitions in endosome and autophagosome maturation. Loss of Ema function leads to increased growth factor signaling due to decreased clearance of ligand bound receptors with resultant synaptic terminal overgrowth. While Clec16a has been suggested to have restricted expression to immune cells, our preliminary evidence indicates that Clec16a is highly expressed in mouse and human islets. Further, loss of function experiments suggest that Clec16a regulates late endosome accumulation, cell replication, insulin secretion, and mitochondrial respiration in ¿-cell lines. Therefore, we hypothesize that Clec16a regulates the ¿ -cell endosomal pathway and the maintenance of ¿-cell mass and function in vivo. Specific Aim I. To test the hypothesis that Clec16a is critical to ¿-cell mass and maintenance of glucose homeostasis. This aim will determine the role of Clec16a via ¿-cell specific loss-of-function experiments in vivo using a conditional Clec16a loxP allele. Experiments will focus on determinations of glucose tolerance and insulin secretion, as well as morphologic analysis of ¿-cell mass related to changes in ¿ -cell proliferation and/or survival. Specific Aim II. To test the hypothesis that the Pdx1 target Clec16a regulates essential aspects of endosome, autophagosome, and mitochondrial function. Experiments will determine the role of Clec16a in endosomal and autophagosome maturation, endosomal trafficking, and mitochondrial biogenesis and calcium flux. In addition, the upstream regulatory role of Pdx1 in regulation of Clec16a and the ¿ -cell endosomal pathway will be determined. Through these specific aims, we will establish the role and functional mechanism for a novel Pdx1 target in the regulation of ¿ -cell mass and function. We will also determine the importance of a target in the endosomal pathway to ¿ -cell function, including insulin secretion, replication/survival, mitochondrial function, and regulation of autophagy, that may open a new areas for future research. PUBLIC HEALTH RELEVANCE: This proposal will focus on discovering the role of Clec16a (KIAA0350), a gene recently identified to be associated with type 1 diabetes in humans. We know very little of the function of this gene in the insulin producing ¿ -cells of the pancreas. We are unsure if loss of this gene leads the ¿ -cells to die or not produce insulin properly. Therefore, our mission is to critically study this gene in order to understand how this gene affects the ¿-cell with hopes that our findings will direct future approaches to treat diabetes.

描述（由申请人提供：本提案详细介绍了医学博士斯科特·索莱曼普尔（Scott Soleimanpour）的研究和培训计划，以发展他作为医师科学家的学术生涯，重点是彻底了解调节胰腺细胞复制和存活的因素，最终目标拟议的 K08 奖项的职业发展部分包括在主要导师 Doris A. Stoffers 的监督下提供高级教学课程和正式研究指导。宾夕法尼亚大学医学院医学博士、博士、医学副教授和多学科指导委员会提供了一个丰富的研究环境，可以向各种专家开放。对 Soleimanpour 博士的科学和专业发展有益的师资和资源本 K08 申请中提出的研究将重点关注 Clec16a（C-凝集素结构域家族 16，成员 A）的 ¿ 细胞特异性作用。 1 型糖尿病易感基因和必需的新靶标 ¿ -细胞转录因子 Pdx1。Clec16a 的果蝇同源物 Ema 是一种内体蛋白，通过与 Vps-C HOPS 复合物直接相互作用，对内体成熟至关重要，该复合物调节内体和自噬体成熟的关键转变，导致 Ema 功能丧失。由于配体结合受体的清除减少导致生长因子信号传导，从而导致突触末端过度生长，而 Clec16a 被认为对免疫表达有限。细胞中，我们的初步证据表明 Clec16a 在小鼠和人类胰岛中高表达，此外，功能丧失实验表明 Clec16a 调节晚期内体积累、细胞复制、胰岛素分泌和线粒体呼吸。 -细胞系。因此，我们认为 Clec16a 调节 ¿ -细胞内体途径和维持 ¿ - 体内细胞质量和功能具体目标 I. 检验 Clec16a 对 ¿ 至关重要的假设。 -细胞质量和葡萄糖稳态的维持这一目标将通过 ¿ 确定 Clec16a 的作用。 -使用条件性 Clec16a loxP 等位基因进行体内细胞特异性功能丧失实验。实验将侧重于葡萄糖耐量和胰岛素分泌的测定，以及 ¿ -与 ¿ 变化相关的细胞质量- 细胞增殖和/或存活。测试 Pdx1 靶标 Clec16a 调节内体、自噬体和线粒体功能的假设。实验将确定 Clec16a 在内体和自噬体成熟、内体运输和功能中的作用。此外，Pdx1 在 Clec16a 和 ¿ 调节中的上游调节作用。通过这些具体目标，我们将确定新的 Pdx1 靶标在 ¿ 调节中的作用和功能机制。 -细胞质量和功能。我们还将确定内体途径中靶标的重要性。 -细胞功能，包括胰岛素分泌、复制/生存、线粒体功能和自噬调节，这可能为未来的研究开辟一个新领域。公共健康相关性：该提案将重点发现 Clec16a (KIAA0350) 的作用，这是一种最近被发现与人类 1 型糖尿病相关的基因，我们对该基因在胰岛素产生中的功能知之甚少。 -胰腺细胞，我们不确定该基因的缺失是否会导致 ¿ -细胞死亡或无法正常产生胰岛素，因此，我们的任务是批判性地研究该基因，以了解该基因如何影响 ¿ -cell希望我们的发现能够指导未来治疗糖尿病的方法。