Insulin, beta-Arrestin 1, and GPCR Signaling

Hupfeld博士是一名受过临床训练的内科医生和内分泌学家，他的长期职业目标包括在糖尿病领域进行基础科学研究，并在一所大学医学院任教。拟议的资助期将使他能够充分发展作为一名独立科学家使用的研究技能。此次培训将在曾傑瑞·奥列夫斯基在加州大学(圣地亚哥)的实验室的卓越环境中进行，奥列夫斯基博士担任导师。通过每周一次的实验室会议，奥列夫斯基博士的密切监督，以及与奥列夫斯基实验室中许多有才华的研究人员的无数互动，哈普菲尔德博士将获得糖尿病研究方面的出色培训。 β-arrestin 1是参与G蛋白偶联受体(GPCR)信号调节的关键蛋白。β-arrestin 1与许多GPCRs的结合导致Gs介导的信号转导的脱敏。我们发现，胰岛素治疗导致β-arrestin 1功能障碍，这与β2肾上腺素能受体对Gs介导的信号的脱敏受损有关，这一发现对II型糖尿病的血脂异常具有潜在的意义。β-arrestin 1在许多GPCRs的促有丝分裂信号中也是重要的。我们已经发现，胰岛素诱导的β-arrestin 1功能障碍阻断了三个GPCRs的有丝分裂信号：β2肾上腺素能受体、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，可以改变几个GPCR的信号传递能力。由于GPCR信号的失调可能是胰岛素抵抗综合征和II型糖尿病许多组成部分背后的致病因素，而胰岛素诱导的β-arrestin 1功能障碍可以影响 对于各种各样的GPCRs的信号程序，我们觉得这是一个重要的新研究领域。因此，这项建议的长期目标是1)扩大我们对胰岛素抵抗综合征背后机制的了解，2)在世界知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。

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.