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（由申请人提供）：β细胞在足以清除高血糖的动态范围内分泌胰岛素[葡萄糖刺激的胰岛素分泌（GSIS）]，但导致血糖升高；这需要胰岛素储存和分泌之间的紧密协调，尽管微管被认为是直接轨道，但我们建议检验我们的假设，即细胞骨架聚合物微管是胰岛素颗粒分配的总体协调者。对于胰岛素颗粒向细胞边缘的运输，我们意外地发现微管隐含地施加负GSIS调节，我们的初步数据表明高葡萄糖刺激会导致动态重排。在拟议的实验中，我们将确定微管网络抑制胰岛素颗粒的机制以及调节这种抑制的生理线索，我们计划剖析微管重塑在 GSIS 调节中的位置。通过研究哪些葡萄糖依赖性信号通路和哪些微管调节分子对于这一过程至关重要。由于 β 细胞功能障碍是导致 T2DM 的重要因素，我们将测试微管是否存在。重排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。总体而言，该提案将揭示微管网络在 β 细胞中的新作用，其范围远远超出了颗粒的简单运输。确定：(1) MT 调节胰岛素颗粒释放的有效性的机制；(2) 触发 MT 不稳定的葡萄糖下游途径和机制；以及 (3) 控制胰岛素颗粒下游的途径和机制；高尔基体衍生的 MT 成核作用将由 Kaverina 博士和 Gu 的实验室密切合作进行，这两个实验室分别专门研究 MT 生物学和 β 细胞发育和功能。