Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy

肌管蛋白 PI 3-磷酸酶在脱髓鞘性周围神经病中的作用

基本信息

批准号：
7467969
负责人：
FRED L ROBINSON
金额：
$ 8.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7467969
关键词：
Affect Biochemical Biology California Cancer Biology Cell physiology Cellular biology Charcot-Marie-Tooth Disease Collection Complex Defect Demyelinations Development Disease Endocytosis Etiology Family Genes Homeostasis Inherited Institution Intervention Laboratories Lead Limb structure Lipids Membrane Membrane Protein Traffic Mentors Metabolism Modeling Motor Mus Muscle Mutation Myelin Sheath Nerve Neurosciences Pathology Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Diseases Pharmacology Phase Phosphatidylinositols Phosphoric Monoester Hydrolases Post-Translational Protein Processing Process Proteins Research Research Personnel Role Schwann Cells Sensory Signal Transduction Supervision Testing Therapeutic Training Transmembrane Transport United States Universities Work design disease-causing mutation medical schools member mouse model myelination myotubularin nervous system disorder phosphatidylinositol 3,5-diphosphate phosphatidylinositol 3-phosphate programs trafficking

项目摘要

DESCRIPTION (provided by applicant): The Candidate, Dr. Fred Robinson, has been training for the last four years as a fellow in the laboratory of Dr. Jack Dixon. Dr. Dixon's Laboratory is in the Department of Pharmacology at the University of California San Diego (UCSD) School of Medicine. UCSD is a renowned research institution, particularly strong in the fields of neuroscience, signal transduction and cancer biology. Dr. Dixon is a world leader in the study of protein and lipid phosphatases. The Candidate has established a fledgling research program focused on understanding how mutations in myotubularin family phosphoinositide (PI) 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT is the most common inherited neurological disorder, affecting about 1 in 2000 in the United States. CMT causes progressive degeneration of the muscles of the extremities and loss of sensory function. Type 4B CMT (CMT4B) is a severe form of the disease in which the myelin sheaths of peripheral nerves are abnormal. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause CMT4B. The Candidate recently demonstrated that the MTMR2 and MTMR13 PI 3-phosphatases form a membrane-associated complex capable of regulating 3-phosphoinositides. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13, the Candidate has generated Mtmrl 3-deficient mice. The specific aims of the proposal are (1) Validate Mtmrl 3-deficient mice as a model of CMT4B disease, (2) Examine the impact of loss of Mtmrl 3 on Mtmr2 function, and (3) Determine how 3-phosphoinositide homeostasis and endosomal-lysosomal trafficking are perturbed in Mtmrl 3-deficient Schwann cells. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3- phosphoinositides may allow us to consider pharmacological modulation of the pathway as a therapeutic strategy. The initial phase of the work (1-2 years) will be carried under Dr. Dixon's supervision. The Candidate will also be mentored by Dr. Katerina Akassoglou, an expert in peripheral nerve biology and demyelination. This phase will focus on characterization of Mtmrl 3-deficient mice and on other aspects of the project for which key training is available at UCSD. Later, as an independent investigator, the Candidate will continue studying Mtmrl 3-deficient mice, focusing more specifically on Schwann cell biology.

描述（由申请人提供）：候选人 Fred Robinson 博士在过去四年中一直作为 Jack Dixon 博士实验室的研究员接受培训。 Dixon 博士的实验室位于加州大学圣地亚哥分校 (UCSD) 医学院药理学系。加州大学圣地亚哥分校是著名的研究机构，在神经科学、信号转导和癌症生物学领域尤其强大。 Dixon 博士是蛋白质和脂质磷酸酶研究领域的世界领先者。该候选人已建立了一项新兴研究计划，重点是了解肌管蛋白家族磷酸肌醇 (PI) 3-磷酸酶的突变如何导致腓骨肌萎缩症 (CMT) 周围神经病。 CMT 是最常见的遗传性神经系统疾病，在美国影响大约 2000 分之一。 CMT 会导致四肢肌肉进行性退化和感觉功能丧失。 4B 型 CMT (CMT4B) 是一种严重的疾病，周围神经髓鞘异常。肌管蛋白相关蛋白 2 (MTMR2) 或 MTMR13 基因突变会导致 CMT4B。该候选人最近证明，MTMR2 和 MTMR13 PI 3-磷酸酶形成能够调节 3-磷酸肌醇的膜相关复合物。由于 MTMR2 或 MTMR13 的缺失足以导致 CMT4B，因此 MTMR13 可能是 MTMR2 的重要调节因子。为了进一步探讨 MTMR2 和 MTMR13 之间的关系，候选者培育了 Mtmrl 3 缺陷小鼠。该提案的具体目标是 (1) 验证 Mtmrl 3 缺陷小鼠作为 CMT4B 疾病模型，(2) 检查 Mtmrl 3 缺失对 Mtmr2 功能的影响，以及 (3) 确定 3-磷酸肌醇稳态和内体-Mtmrl 3 缺陷的雪旺细胞中的溶酶体运输受到干扰。了解施万细胞内体-溶酶体途径如何通过 3-磷酸肌醇的失调而改变，可以使我们将该途径的药理学调节视为一种治疗策略。工作的初始阶段（1-2年）将在Dixon博士的监督下进行。候选人还将得到周围神经生物学和脱髓鞘专家 Katerina Akassoglou 博士的指导。此阶段将重点关注 Mtmrl 3 缺陷小鼠的表征以及 UCSD 提供关键培训的项目的其他方面。随后，作为一名独立研究者，候选人将继续研究 Mtmrl 3 缺陷小鼠，更具体地关注雪旺细胞生物学。