The Role of Clec16a in the Pancreatic Islet

Clec16a 在胰岛中的作用

• 批准号: 8594240
• 负责人: Scott Soleimanpour
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8594240
• 关键词: Affect; Alleles; Area; Autophagocytosis; Autophagosome; Award; Biogenesis; Biological Assay; Cell Line; Cell Maintenance; 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; Islet Cell; 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

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.

描述（由应用程序提供：该建议详细介绍了Scott Soleimanpour的研究和培训计划，M.D。旨在发展他作为身体科学家的学术生涯，重点是对调节胰腺复制和生存的因素的透彻理解，并以1型糖尿病的形式培训奖励的最终培训，包括拟议的K08奖项。宾夕法尼亚大学医学院的医学副教授，多学科的心理学委员会，宾夕法尼亚大学医学院的主要精神，医学博士学位，博士学位。 K08的应用将重点放在CLEC16A（C-结构素域家族16，成员A），1型糖尿病敏感性基因和必需细胞转录因子PDX1的新目标的特定作用上。 CLEC16A（EMA）的果蝇直系同源物是通过与VPS-C HOPS复合物直接相互作用的内体成熟至关重要的内体蛋白，该蛋白质与VPS-C HOPS复合物进行了直接相互作用，该复合体调节了内体和自噬体成熟的关键过渡。 EMA功能的丧失会导致由于配体结合受体的清除率降低而导致生长因子信号的增加，从而导致突触末端过度生长。尽管已建议CLEC16A对免疫细胞具有限制的表达，但我们的初步证据表明Clec16a在小鼠和人类胰岛中高度表达。此外，功能实验的丧失表明CLEC16A调节内体积累，细胞复制，胰岛素分泌和线粒体呼吸 - 细胞线。因此，我们假设CLEC16A调节 - 细胞内体途径，并在体内维持 - 细胞质量和功能。具体目的I.为了检验CLEC16A对质量质量和葡萄糖稳态维持至关重要的假设。该目标将通过条件CLEC16A LOXP等位基因在体内通过特异性功能丧失实验来确定CLEC16A的作用。实验将集中于确定葡萄糖耐受性和胰岛素分泌，以及与细胞增殖和/或生存变化有关的细胞质量的形态分析。具体目标II。为了测试PDX1靶标CLEC16A调节内体，自噬体和线粒体功能的基本方面的假设。实验将确定CLEC16A在内体和自噬体成熟，内体运输以及线粒体生物发生和钙通量中的作用。另外，将确定PDX1在CLEC16A和� -CELL内体途径的调节中的上游调节作用。通过这些具体目标，我们将在调节``细胞质量和功能''中建立新型PDX1目标的作用和功能机制。我们还将确定目标在内体途径中的重要性 - 细胞功能，包括胰岛素分泌，复制/生存，线粒体功能以及自噬的调节，这可能为未来的研究打开新领域。