Insulin, beta-Arrestin 1, and GPCR Signaling

Hupfeld博士是一名临床训练有素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的研究技能。本次培训将在加州大学圣地亚哥分校杰瑞·奥莱夫斯基实验室的优秀环境中进行，由奥莱夫斯基博士担任导师。通过每周一次的实验室会议，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次互动，Hupfeld博士将在糖尿病研究方面得到出色的培训。

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.