Pathogenesis and Diagnosis of Multiple System Atrophy (P01)

描述(由申请人提供)：MSA是一种以帕金森症或小脑功能障碍和自主功能衰竭为特征的持续进行性和致命的疾病。该PPG由已故的克里夫·舒尔茨博士创立，致力于MSA的发病机制和治疗研究。从过去5年中收集的成功和见解使我们能够将竞争对手的续订提案整合、修改和改进为3个紧密集成的核心和4个具有重要和可实现终点的项目。我们已经实现了招募175名MSA患者的最初目标。初步数据使我们将项目1从流行病学研究(已经完成)修改为正在进行的前瞻性研究，以确定结果的预测因素。具体地说，项目1(Oilman)将测试发病时临床表型和自主神经症状预测临床病程的假设。这一MSA患者队列将扩大到275名患者，增加100名病情较轻和更早的MSA患者。项目1还将使用心脏的高分辨率PET扫描，研究心脏的肾上腺素能神经支配([llCj羟基麻黄碱标记])。项目2(Benarroch)将对下丘脑的关键神经元群进行形态计量免疫组织化学研究。马斯利亚博士将继续关注MSA的分子发病机制。他开发了一种模仿人类MSA的转基因小鼠模型，带有胶质细胞质包涵体(GCI)和神经元丢失。他继续学习以增加或逆转GCI和行为缺陷。Benarroch博士将把他对相关核团和GCI的形态计量分析应用到这个小鼠模型中。刘特佐博士将继续他对实验室自主神经指标的前瞻性研究，这是一个更进步的过程。此外，他还将进行一项双盲安慰剂对照研究，以评估一种在不恶化仰卧位高血压的情况下改善直立性低血压的新方法。一项关键的大型先导性研究将集中在利福平的治疗试验上，根据项目3的结果，该试验可能会阻止MSA的进展或逆转其发病机制。这项研究将由项目1和4联合进行，并得到核心A的支持。这些项目将继续得到3个核心的支持。

DESCRIPTION (provided by applicant): MSA is a relentlessly progressive and fatal disease characterized by parkinsonism or cerebellar dysfunction and autonomic failure. This PPG, founded by the late Dr. Cliff Shults, is devoted to studies on the pathogenesis and management of MSA. The success and insights gleaned from the last 5 years has enabled us to consolidate, modify, and improve the competing renewal proposal into 3 tightly integrated Cores and 4 Projects with important and achievable endpoints. We have achieved our original goal of recruiting 175 patients with MSA. Preliminary data has led us to modify Project 1 from an epidemiologic study (which has been completed) to an ongoing prospective study that will identify predictors of outcome. Specifically, Project 1 (Oilman) will test the hypothesis that clinical phenotype at onset and autonomic symptoms are predictive of clinical course. This MSA patient cohort will be expanded to 275 patients, by adding 100 additional patients with milder and earlier MSA. Project 1 will additionally study adrenergic innervation of the heart ([llCjhydroxyephedrine labeling), using high resolution PET scanning of the heart. Project 2 (Benarroch) will undertake a morphometric immunohistochemical study on key neuronal groups in hypothalamus. Dr. Masliah will continue his focus on the molecular pathogenesis of MSA. He has developed a transgenic mouse model that mimics human MSA, with glial-cytoplasmic inclusion (GCI) and neuronal loss. He continues his studies to increase or reverse GCI and behavioral deficits. Dr. Benarroch will apply his morphometric analysis of relevant nuclear groups and GCI to this mouse model. Dr. Low will continue his prospective study of laboratory autonomic indicators of a more progressive course. He will additionally undertake a double-blind placebo controlled study to evaluate a novel approach to improving orthostatic hypotension without worsening supine hypertension. A key large pilot study will focus on a treatment trial of Rifampicin, which could potentially halt progression or reverse the pathogenesis of MSA, based on results from Project 3. The study will be conjointly carried out by Projects 1 and 4 and supported by Core A. These projects will continue to be supported by 3 cores.