Aberrant activation of mTOR in peripheral neuropathy

周围神经病变中 mTOR 的异常激活

基本信息

批准号：
7913904
负责人：
Sean Hagerty
金额：
$ 4.13万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this application is to elucidate the role of mTOR signaling in Charcot-Marie-Tooth 1A (CMT1A) disease onset and progression. In particular, we will focus on the potential contribution of aberrant mTOR activity to the dedifferentiation/dysmyelination of Schwann cells that is the hallmark of CMT, and in complementary studies, examine the potential of rapamycin as a novel therapeutic strategy in CMT1A in vivo. The misexpression of myelin proteins is a characteristic feature of most inherited neuropathies. Signaling pathways are activated in response to myelin protein misexpression; these are likely to contribute to the Schwann cell pathology in these disorders but remain incompletely characterized. Previous results strongly suggest that overexpression of PMP22 in CMT1A leads to mTOR activation which, in turn, results in Schwann cell dedifferentiation. Thus, inhibition of mTOR with rapamycin rescues myelination in a tissue culture model of CMT1A. These results indicate mTOR activation is necessary to induce Schwann cell dedifferentiation in CMT1A; it is not known whether it is sufficient. The three specific aims proposed further seek to characterize the role of mTOR in Schwann cell dedifferentiation in CMT1A. In particular, aim one will determine if activation of mTOR is sufficient to induce Schwann cell dedifferentiation and demyelination. Aim two will investigate how PMP22 overexpression results in activation of the mTOR pathway and subsequent Schwann cell dedifferentiation. Aim three will examine the effects of rapamycin treatment of PMP22 transgenic overexpressing rats, a model of CMT1A. CMT1A is the most common inherited neuropathy, affecting 1 in 2500 people; currently, there are no effective therapeutics for this disorder. These studies should provide important new insights into the signaling pathways activated in CMT, in particular mTOR, and determine the potential of rapamycin as a novel therapeutic strategy in CMT1A in vivo. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy, affecting 1 in 2500 people; currently, there are no effective therapeutics for this disorder. We have identified a novel therapeutic target for CMT1A. If awarded this fellowship, we would utilize a well characterized murine model of CMT1A to apply our therapeutic strategy in vivo and elucidate the molecular mechanisms responsible for disease onset and progression. By identifying the pathways responsible for Schwann cell dedifferentiation, our work may have wide-ranging applications in the development of treatments for other inherited peripheral neuropathies.

描述（由申请人提供）：该应用的长期目标是阐明MTOR信号在charcot-marie-tooth 1a（CMT1A）疾病发作和进展中的作用。特别是，我们将重点关注异常活性对CMT的标志的Schwann细胞的去分化/降解症的潜在贡献，在互补研究中，研究了雷帕霉素作为VIVO中CMT1A中新型治疗策略的潜力。髓磷脂蛋白的表现是大多数遗传神经病的特征。信号通路会响应髓磷脂蛋白膜而激活。这些可能有助于这些疾病中的雪旺细胞病理学，但仍未完全表征。先前的结果强烈表明，CMT1A中PMP22的过表达导致MTOR激活，从而导致Schwann细胞去分化。因此，用雷帕霉素抑制MTOR在CMT1A的组织培养模型中挽救了髓鞘化。这些结果表明，MTOR激活对于诱导CMT1A中的Schwann细胞去分化是必要的。目前尚不清楚这是否足够。提出的三个具体目标进一步寻求表征MTOR在CMT1A中Schwann细胞去分化的作用。特别是，AIM将确定MTOR的激活是否足以诱导Schwann细胞去分化和脱髓鞘。目标两个将研究PMP22的过表达如何导致MTOR途径的激活和随后的Schwann细胞去分化。 AIM三将检查雷帕霉素对PMP22转基因过表达大鼠的影响，这是CMT1A模型。 CMT1A是最常见的神经病，影响了2500人中的1人；目前，这种疾病还没有有效的治疗疗法。这些研究应提供有关CMT中激活的信号通路的重要新见解，特别是MTOR，并确定雷帕霉素是体内CMT1A中新型治疗策略的潜力。公共卫生相关性：项目叙事charcot-marie-tooth 1a（CMT1A）是最常见的神经病，影响了2500人中的1人；目前，这种疾病还没有有效的治疗疗法。我们已经确定了CMT1A的新型治疗靶标。如果授予该研究金，我们将利用CMT1A的鼠模型来应用我们的治疗策略，并阐明负责疾病发作和进展的分子机制。通过确定负责Schwann细胞去分化的途径，我们的工作可能在开发其他遗传性周围神经病的治疗方面具有广泛的应用。