Light Activation of Retinal Insulin Receptor Signaling

描述（由申请人提供）：长期目标是了解胰岛素受体（IR）在视网膜中的作用，并阐明它们产生的细胞内信号通路。该提案的总体目标是获得对光感受器功能控制的新理解。具体的目的是研究视网膜IR在光感受器结构和功能调节中的作用。我们的新发现，光刺激酪氨酸磷酸化的b-亚基的IR在体内，反过来，激活磷酸肌醇3-激酶，细胞存活因子。光效应局限于光感受器神经元，并且不依赖于胰岛素分泌。我们已经确定了Grb 14的IR（IR）的上游调节需要光漂白的视紫红质膜靶向。此外，Grb 14是蛋白酪氨酸磷酸酶PTP 1 B b的抑制剂，其特异性地使IR去磷酸化。这些观察结果导致以下假设：光信号启动Grb 14定位于光感受器外节膜，这导致PTP 1 B的抑制，从而导致IR磷酸化的保护。因此，光诱导的IR活化促进光感受器存活和维持。新发现的通路可能在感光细胞信号传导的其他方面有影响。以下具体目标旨在测试我们的中心假设，即光诱导的IR激活对于正常感光细胞的存活和维持是重要的。目的1是确定感光细胞中的IR是否是光激活生存途径所必需的。目的2：探讨Grb 14和PTP 1b调节胰岛素抵抗的机制。目的3是确定视杆细胞光依赖性转位所需的Grb 14的结构域。我们将利用遗传，分子和生物化学方法的组合，以解决新的生物学途径。总之，这些研究将为光受体结构和功能的分子调控提供新的见解。所获得的信息对于理解视杆细胞中新发现的通路的新生物学将是重要的。这些研究结果将有助于更好地了解视网膜变性的机制，并为未来的治疗干预提供指导。其生物学意义延伸到许多视网膜退行性疾病的病因和治疗。

DESCRIPTION (provided by applicant): The long term goal is to understand the role of insulin receptors (IR) in the retina and elucidate the intracellular signaling pathways they generate. The overall goal of this proposal is to gain new understanding of the control of photoreceptor function. The specific objective is to investigate the role of the retinal IR in regulation of photoreceptor structure and function. We made the novel finding that light stimulates tyrosine phosphorylation of the b-subunit of IR in vivo, and, in turn, activate phosphoinositide 3-kinase, a cell survival factor. The light effect is localized to photoreceptor neurons and is independent of insulin secretion. We have identified Grb14 an upstream regulator of IR (IR) requires photobleaching of rhodopsin for membrane targeting. Further Grb14 is an inhibitor of protein tyrosine phosphatase PTP1 b which specially dephosphorylates the IR. These observations led to the hypothesis that a light signal initiates the localization of Grb14 to photoreceptor outer segment membranes which leads to the inhibition of PTP1 b resulting in the protection of IR phosphorylation. Thus, the light-induced IR activation promotes photoreceptor survival and maintenance. The newly discovered pathway may have implications in other aspects of photoreceptor signaling. The following specific aims are designed to test our central hypothesis that light-induced activation of IR is important for normal photoreceptor survival and maintenance. Aim 1 is to determine whether the IR in photoreceptor cells is necessary for light activation of survival pathways. Aim 2 is to determine the mechanism of regulation of the IR by Grb14 and PTP1b. Aim 3 is to determine the domains of Grb14 that are required for light-dependent translocation in rod photoreceptor cells. We will utilize a combination of genetic, molecular and biochemical approaches to address the novel biology of the pathway. Together, these studies will provide novel insights into the molecular regulation of photoreceptor structure and function by light. The information gained will be important for understanding the novel biology of the newly discovered pathway in rod photoreceptor. Results of these studies will help better understanding the mechanism of retinal degenerations and guide targets for future therapeutic intervention. The biological implications extend to the cause and treatment of a number of retinal degenerative diseases.