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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.