Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy

描述(由申请人提供)： 候选人弗雷德·罗宾逊博士在过去四年里一直在杰克·迪克森博士的实验室里接受培训。迪克森博士的实验室位于加州大学圣地亚哥分校(UCSD)医学院的药理学系。加州大学圣迭戈分校是一家著名的研究机构，在神经科学、信号转导和癌症生物学领域尤其强大。迪克森博士是蛋白质和脂肪磷酸酶研究的世界领先者。这位候选人已经建立了一个羽翼未丰的研究计划，专注于了解肌管蛋白家族磷脂酰肌醇(PI)3-磷酸酶突变是如何导致Charcot-Marie-Tooth(CMT)周围神经病的。CMT是最常见的遗传性神经疾病，2000年在美国约有1人患病。CMT会导致四肢肌肉的进行性退化和感觉功能的丧失。4B型CMT(CMT4B)是一种周围神经髓鞘异常的严重疾病。肌管蛋白相关蛋白2(MTMR2)或MTMR13的基因突变会导致CMT4B。这位候选人最近证明了MTMR2和MTMR13PI 3-磷酸酶形成了一个膜相关的复合体，能够调节3-磷酸肌醇。由于MTMR2或MTMR13的缺失足以引起CMT4B，MTMR13可能是MTMR2的重要调节因子。为了进一步探索MTMR2和MTMR13之间的关系，候选人产生了MTMR1 3缺陷小鼠。该提案的具体目的是：(1)验证Mtmrl3缺陷小鼠作为CMT4B疾病模型的有效性；(2)检测Mtmrl3缺失对Mtmr2功能的影响；(3)确定Mtmrl3缺陷雪旺细胞中3-磷酸肌醇稳态和内体-溶酶体转运是如何被扰乱的。了解3-磷酸肌醇的失调是如何改变雪旺细胞内切酶-溶酶体途径的，可能会使我们考虑将药物调节该途径作为一种治疗策略。 这项工作的初始阶段(1-2年)将在迪克森博士的监督下进行。候选人还将得到周围神经生物学和脱髓鞘专家卡特琳娜·阿卡索格鲁博士的指导。这一阶段将侧重于Mtmrl 3缺陷小鼠的特征以及加州大学可持续发展分校为其提供关键培训的项目的其他方面。稍后，作为一名独立研究员，候选人将继续研究Mtmrl 3缺陷小鼠，更具体地说，专注于雪旺细胞生物学。

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.