Microtubule Regulation of Pancreatic Beta Cell Function and Diabetes

 描述（由申请人提供）：β细胞分泌胰岛素的动态范围足以清除高血糖[葡萄糖刺激的胰岛素分泌（GSIS）]，但导致 无低血糖;这需要胰岛素颗粒储存和分泌之间的紧密协调。在这个合作项目中，我们提出来检验我们的假设，即细胞骨架聚合物微管是胰岛素颗粒分配到储备池和容易释放池的总体协调者。虽然微管被认为是胰岛素颗粒运输到细胞边缘的直接通道，但我们意外地发现微管对GSIS具有负调节作用。有趣的是，我们的初步数据表明，高葡萄糖刺激引起MT网络的动态重排，这使得胰岛素颗粒可供释放。在本实验中，我们将探讨微管网络对胰岛素颗粒的抑制机制，以及调节这种抑制的生理因素。我们计划通过研究哪种葡萄糖依赖性信号通路和哪种微管调节分子对这一过程至关重要来剖析微管重塑在GSIS调节中的位置。由于β细胞功能障碍是导致T2 DM的一个重要因素，我们将测试微管重排是否在疾病发展中发挥作用，以及微管是否可以作为糖尿病治疗中的药物靶点。总的来说，这一提议将揭示β细胞中微管网络的新作用，其远远超出了颗粒的简单运输。我们的具体目标将确定：（1）MT调节胰岛素颗粒释放可用性的机制;（2）触发MT不稳定的葡萄糖下游途径和机制;（3）控制高尔基体衍生MT成核的葡萄糖下游途径和机制。这项研究将作为Kaverina博士和Gu实验室之间的密切合作进行，他们分别专注于MT生物学和β细胞发育和功能。

 DESCRIPTION (provided by applicant): β-Cells secrete insulin within a dynamic range sufficient to clear high blood sugar [glucose-stimulated insulin secretion (GSIS)] but resulting in no hypoglycemia; this requires tight coordination between insulin granule storage and secretion. In this collaborative project, we propose to test our hypothesis that cytoskeletal polymers microtubules are overall coordinators of insulin granule allocation to reserve versus readily- releasable pools. Though microtubules have been considered as direct tracks for insulin granule transport to the cell edge, we unexpectedly found that microtubules exert negative GSIS regulation. Interestingly, our preliminary data indicate that high glucose stimuli cause dynamic rearrangement of the MT network, which makes insulin granules available for release. In the proposed experiments, we will determine the mechanisms of insulin granule restrain by microtubule network and physiological cues that modulate this restrain. We plan to dissect the place of microtubule remodeling in GSIS regulation by studying which glucose-dependent signaling pathway(s) and which microtubule-regulating molecule(s) are essential for this process. Since β-cell dysfunction is a strong factor contributing to T2DM, we will test whether microtubule rearrangements play a role in disease development, and whether microtubules might serve as druggable targets in diabetes therapies. Overall, this proposal will reveal a new role for the microtubule network in β cells, which extends far beyond simple transportation of granules. Our Specific Aims will determine: (1) the mechanisms whereby MTs regulate the availability of insulin granules for release; (2) pathways and mechanisms downstream of glucose that trigger MT destabilization; and (3) pathways and mechanisms downstream of glucose that control Golgi-derived MT nucleation. This study will be pursued as a close collaboration between Dr. Kaverina's and Gu's laboratories, who specialize in MT biology and β-cell development and function, respectively.