Microtubule Regulation of Pancreatic Beta Cell Function and Diabetes

胰腺β细胞功能和糖尿病的微管调节

基本信息

批准号：
9229554
负责人：
Guoqiang Gu
金额：
$ 60.11万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229554
关键词：
AKAP9 gene Actins Acute Algorithms Alpha Granule B-Cell Development Beta Cell Biology Blood Glucose Cell physiology Cells Cellular Stress Chemicals Collaborations Computer Simulation Cues Cytoplasmic Granules Cytoskeleton Data Development Diabetes Mellitus Diabetic mouse Disease Equilibrium Failure Fostering Functional disorder Glucose Goals Golgi Apparatus Heterogeneity Human Hypoglycemia Insulin Laboratories Maps Microtubule Depolymerization Microtubule Stabilization Microtubules Modeling Molecular Motors Motor Movement Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Peripheral Phosphorylation Physiological Play Polymers Positioning Attribute Process Production Regulation Research Resolution Role Rosaniline Dyes Signal Pathway Signal Transduction Site Stimulus Structure Structure of beta Cell of islet Testing Time Transportation Tubulin Withdrawal blood glucose regulation density design diabetes mellitus therapy experimental study genetic manipulation glucose metabolism inhibitor/antagonist insulin granule insulin secretion islet katanin novel novel strategies prevent public health relevance response

项目摘要

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.

描述（通过应用提供）：β细胞在动态范围内的β细胞秘密胰岛素足以清除高血糖[葡萄糖刺激的胰岛素分泌（GSIS）]，但导致没有低血糖；这需要在胰岛素颗粒储存和分泌之间进行紧密的协调。在这个合作项目中，我们建议测试我们的假设，即细胞骨架聚合物微管是胰岛素颗粒分配的总体协调员，以储备与易于易用的池。尽管微管被认为是胰岛素颗粒转运到细胞边缘的直接轨道，但我们出乎意料地发现微管会施加负GSIS调节。有趣的是，我们的初步数据表明高葡萄糖刺激会导致MT网络的动态重排，这使得胰岛素颗粒可用于释放。在拟议的实验中，我们将通过微管网络和调节这种约束的物理提示来确定胰岛素颗粒限制的机制。我们计划通过研究哪些葡萄糖依赖性信号通路（S）和哪些微管调节分子（S）对于此过程至关重要。由于β细胞功能障碍是导致T2DM的重要因素，因此我们将测试微管重排是否在疾病发育中起作用，以及微管是否可以作为糖尿病疗法中的可药物靶标。总体而言，该提案将揭示β细胞中微管网络的新作用，β细胞远远超出了颗粒的简单运输。我们的具体目的将确定：（1）MTS调节胰岛素颗粒释放的机制；（2）葡萄糖下游的途径和机制引发MT不稳定；（3）葡萄糖下游的途径和机制控制高尔基衍生的MT成核。这项研究将作为Kaverina博士和GU的实验室之间的密切合作，分别专门研究MT生物学和β细胞的发展和功能。