Insulin, beta-Arrestin 1, and GPCR Signaling

Hupfeld博士是一名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和在大学医学院任教。拟议的资助期将使他能够充分发展作为独立科学家的研究技能。该培训将在加州大学（圣地亚哥）Jerry Olefsky实验室的出色环境中进行，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实验室许多有才华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。 β-抑制蛋白1是参与G蛋白偶联受体（GPCR）信号转导调节的关键蛋白。β-抑制蛋白1与许多GPCR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β 2肾上腺素能受体介导的Gs信号转导的脱敏受损有关，这一发现对II型糖尿病的血脂异常具有潜在意义。β-抑制蛋白1在促进许多GPCR的促有丝分裂信号传导中也很重要。我们发现胰岛素诱导的β-arrestin 1功能障碍通过三种GPCR阻断促有丝分裂信号传导：β 2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，可以改变几种GPCR的信号传导能力。由于GPCR信号传导的失调是胰岛素抵抗综合征和II型糖尿病的许多组分背后的可能病因因素，并且胰岛素诱导的β-抑制蛋白1功能障碍可以影响胰岛素抵抗综合征和II型糖尿病的发病机制。 信号程序的各种GPCR，我们觉得这是一个重要的新的研究领域。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）在世界知名的糖尿病研究实验室内为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.