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。本提案的总体目标是获得对光感受器功能控制的新认识。具体目的是研究视网膜IR在光感受器结构和功能调节中的作用。我们的新发现是，光刺激体内IR b亚基的酪氨酸磷酸化，进而激活磷酸肌肽3-激酶，这是一种细胞存活因子。光效应局限于光感受器神经元，与胰岛素分泌无关。我们已经确定Grb14是IR的上游调节剂（IR）需要光漂白视紫质来进行膜靶向。此外，Grb14是蛋白酪氨酸磷酸酶PTP1 b的抑制剂，其特异性地使IR去磷酸化。这些观察结果导致了一种假设，即光信号启动Grb14定位到光感受器外段膜，从而抑制PTP1 b，从而保护IR磷酸化。因此，光诱导的IR激活促进了光感受器的存活和维持。新发现的途径可能对光感受器信号传导的其他方面有影响。以下具体目标旨在验证我们的中心假设，即光诱导的IR激活对正常光感受器的存活和维持很重要。目的1是确定光感受器细胞中的IR是否是光激活生存途径所必需的。目的2是确定Grb14和PTP1b调控IR的机制。目的3是确定Grb14的结构域，这些结构域是杆状光感受器细胞中光依赖性易位所必需的。我们将利用遗传、分子和生化方法的结合来解决该途径的新生物学问题。总之，这些研究将为光对光感受器结构和功能的分子调控提供新的见解。所获得的信息将对理解新发现的杆状光感受器通路的新生物学具有重要意义。这些研究结果将有助于更好地了解视网膜变性的机制，并指导未来治疗干预的目标。生物学意义延伸到一些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.