Insulin, beta-Arrestin 1, and GPCR Signaling

胰岛素、β-抑制蛋白 1 和 GPCR 信号转导

• 批准号: 7239561
• 负责人: CHRISTOPHER J HUPFELD
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239561
• 关键词: Adrenergic Receptor; Affect; Area; Arrestin Beta 1; Basic Science; Binding; California; Cells; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Dominant-Negative Mutation; Dyslipidemias; Educational process of instructing; Endocrinologist; Environment; Functional disorder; Funding; G Protein-Coupled Receptor Genes; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Insulin; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Internist; Knowledge; Laboratories; Laboratory Research; Lysophosphatidic Acid Receptors; Mediating; Mentors; Mitogen-Activated Protein Kinases; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Phosphorylation; Process; Proteins; Regulation; Reporter; Research; Research Personnel; Research Training; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Supervision; Syndrome; Techniques; Testing; Training; Universities; arrestin 1; career; desensitization; inhibitor/antagonist; medical schools; novel; programs; skills; src-Family Kinases

Dr. Hupfeld is a clinically trained internist and endocrinologist, whose long-term career goals include conducting basic science research in the field of diabetes mellitus and teaching at a university medical school. The proposed funding period will enable him to fully develop research skills to be used as an independent scientist.. This training will occur in the outstanding environment of Jerry Olefsky's laboratory at the University of California(San Diego), with Dr. Olefsky serving as mentor. Through weekly lab meetings, close supervision by Dr. Olefsky, and the innumerable interactions with the many talented researchers in the Olefsky lab, Dr. Hupfeld will be provided with outstanding training in diabetes research. Beta-arrestin 1 is a critical protein involved in regulation of G protein-coupled receptor(GPCR) signaling. Binding of beta-arrestin 1 to many GPCRs leads to desensitization of Gs-mediated signal transduction. We have found that insulin treatment leads to dysfunction of beta-arrestin 1, and that this was associated with impaired desensitizaton of Gs-mediated signaling by the beta2 adrenergic receptor, a finding that has potential implications for dyslipidemia of type II diabetes mellitus. Beta-arrestin 1 is also important in promoting mitogenic signaling by many GPCRs. We have found that insulin-induced dysfunction of beta-arrestin 1 blocks mitogenic signaling by three GPCRs: the beta2 adrenergic receptor, the LPA receptor, and the IGF-1 receptor. Together, these findings indicate that insulin, through a mechanism involving dysfunction of beta-arrestin 1, can alter the signaling capabilities of several GPCRs. As dysregulation of GPCR signaling is a possible etiologic factor behind many of the components of the insulin resistance syndrome and type II diabetes mellitus, and insulin-induced dysfunction of beta-arrestin 1 can affect the signaling program of a wide variety of GPCRs, we feel this is an important new area of research. Thus the long-term goals of this proposal are 1)to expand our knowledge of the mechanisms behind the insulin resistance syndrome, and 2) to provide outstanding research training for Dr. Hupfeld, in the confines of a world-renowned diabetes research laboratory.

Hupfeld 博士是一位经过临床培训的内科医生和内分泌学家，其长期职业目标包括在糖尿病领域进行基础科学研究以及在大学医学院任教。拟议的资助期限将使他能够充分发展作为独立科学家的研究技能。本次培训将在加州大学（圣地亚哥）Jerry Olefsky 实验室的优越环境中进行，由 Olefsky 博士担任导师。通过每周的实验室会议、Olefsky 博士的密切监督以及与 Olefsky 实验室众多才华横溢的研究人员的无数互动，Hupfeld 博士将获得糖尿病研究方面的出色培训。 Beta-arrestin 1 是参与 G 蛋白偶联受体 (GPCR) 信号传导调节的关键蛋白。 β-arrestin 1 与许多 GPCR 的结合会导致 Gs 介导的信号转导脱敏。我们发现胰岛素治疗会导致 β-arrestin 1 功能障碍，并且这与 β2 肾上腺素受体 Gs 介导的信号传导脱敏受损有关，这一发现对 II 型糖尿病血脂异常具有潜在影响。 Beta-arrestin 1 对于促进许多 GPCR 的有丝分裂信号传导也很重要。我们发现胰岛素诱导的 β-arrestin 1 功能障碍会阻断三种 GPCR 的有丝分裂信号传导：β2 肾上腺素受体、LPA 受体和 IGF-1 受体。总之，这些发现表明，胰岛素通过涉及 β-arrestin 1 功能障碍的机制，可以改变多个 GPCR 的信号传导能力。由于 GPCR 信号传导失调是胰岛素抵抗综合征和 II 型糖尿病许多组成部分背后的可能病因，而胰岛素诱导的 β-arrestin 1 功能障碍可能会影响胰岛素抵抗综合征和 II 型糖尿病的许多组成部分。 我们认为这是一个重要的新研究领域。因此，该提案的长期目标是 1) 扩大我们对胰岛素抵抗综合征背后机制的了解，2) 在世界著名的糖尿病研究实验室的范围内为 Hupfeld 博士提供出色的研究培训。