UNDERSTANDING FXTAS AMONG MALES WITH THE FMR1 PREMUTATION

了解 FMR1 提前突变的男性 FXTAS

• 批准号: 7483335
• 负责人: Stephanie L. Sherman
• 金额: $ 19.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483335
• 关键词: Accelerated Phase; Address; Age; Age of Onset; Age-Years; Ataxia; Autonomic Dysfunction; Behavior Disorders; Budgets; Classification; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive deficits; Cohort Studies; Cross-Sectional Studies; Data; Development; Diagnosis; Disease; Ensure; Erectile dysfunction; Evidence based treatment; FMR1 Premutation; FXTAS; Failure; Family; Fecal Incontinence; Fragile X Syndrome; Functional disorder; Funding; Future; Genetic; Goals; Grant; Impaired cognition; Individual; Institution; Intervention; Laboratories; Longitudinal Studies; Measures; Medical History; Messenger RNA; Motor; Neurodegenerative Disorders; Neurologic; Neuropsychology; Neurosecretory Systems; Parkinsonian Disorders; Participant; Pathology; Patients; Pattern; Phase; Phenotype; Pilot Projects; Population; Population Study; Range; Rate; Recruitment Activity; Relative (related person); Research Personnel; Research Project Grants; Restless Legs Syndrome; Risk; Sampling; Sampling Studies; Screening procedure; Severities; Siblings; Site; Sleep Apnea Syndromes; Snoring; Specific qualifier value; Structure; Symptoms; Testing; Testosterone; Time; Toxic effect; Translational Research; Tremor; Woman; Work; Yang; base; cognitive change; demographics; experience; follow-up; insight; male; men; rapid eye movement; research study; urinary

Dr. Sherman's project will utilize the study population of well-phenotyped FMR1 premutation carrier males and their noncarrier siblings created in the previous funding period to test specific hypotheses that will delineate the disease course of fragile X-associated tremor/ataxia syndrome (FXTAS), a debilitating neurodegenerative disorder. Our current cross-sectional study includes neuropsychologic and neurologic assessments, demographics and medical history obtained from individuals recruited from families identified with fragile X syndrome (FXS). In this funding period, we will extend the phenotype battery to further characterize non-motor symptoms that, in our experience, often pre-date the onset of motor symptoms. We will leverage our existing population to obtain a second follow-up time point in these individuals. We will develop an abbreviated test battery derived from the analysis of the two time points, one that will be more suitable for future longitudinal studies. We are working with other established FXTAS consortia to ensure that this test battery, or a modified version, becomes a deliverable product available for future clinical trials. As this neurodegenerative disorder is known to be incompletely penetrant with variable age of onset, severity and progression, assessment of pre-motor symptoms will be essential if neuroprotective therapy is to be considered in the future. Because of the budgetary constraints of this application and our preliminary data indicating a significantly reduced risk for FXTAS among women, we have proposed a focused clinical research study on males only, but emphasize that this project will serve as a launching pad for future studies. The over-arching goal of this project is to test hypotheses that will provide insight into the pathology and disease course of FXTAS in order to: 1) specify time points for neuroprotective interventions and 2) provide evidence-based treatment strategies of FXTAS-related symptoms. Because of the budget constraints, we have developed a small, focused clinical research project primarily examining non-motor symptoms and their progression, taking advantage of our current study sample. However, we envision this project as a pilot project that can be enhanced within the structure of the Fragile X Center, one that extends the current ongoing projects at Emory and Baylor that address fragile X-associated disorders. For example, our study cohort that has been carefully phenotyped using funding from the current Fragile X Center grant will be available for future studies that examine genetic and environmental modifiers of FXTAS based on exciting data from Dr. Peng Jin's laboratory. Dr. Jin is a young investigator in our department who has contributed significantly to the understanding of the toxic effect of the premutation mRNA (e.g., Duan and Jin, 2006; e.g., Jin et al., 2003; Yang et al., 2007). Our plan is to use data derived from this proposed pilot study and those from other collaborators within our institutions to spin off new projects that have the same basic goal to ameliorate the symptoms of FXTAS. In parallel, we have moved outside our Fragile X Center "walls" and have established a FXTAS Working Group with other investigators who are working on FXTAS. Our goal is to establish phenotype measures that document the course of the disorder, are portable and can be shared across studies being conducted at multiple sites. This data-sharing will be an essential component of future clinical and translational research on FXTAS.

谢尔曼博士的项目将利用表型良好的FMR1前突变携带者男性的研究群体 以及他们在上一个资助期创建的非携带者兄弟姐妹，以测试特定的假设 描述脆性X相关震颤/共济失调综合征(FXTAS)的病程，FXTAS是一种衰弱的疾病 神经退行性疾病。我们目前的横断面研究包括神经心理学和神经学。 从确定的家庭招募的个人获得的评估、人口统计数据和病史 患有脆性X综合征(FXS)。在这一资助期间，我们将进一步扩大表型电池的使用范围 描述非运动性症状，根据我们的经验，这些症状往往早于运动性症状的出现。我们会 利用我们现有的人口，在这些人中获得第二个后续时间点。我们将开发一种 根据对两个时间点的分析得出的简化测试电池，其中一个将更适合 未来的纵向研究。我们正在与其他已建立的FXTAS联盟合作，以确保这项测试 电池，或改良版本，成为可交付产品，可用于未来的临床试验。因为这就是 众所周知，神经退行性疾病是不完全穿透的，具有不同的发病年龄、严重程度和 如果要进行神经保护治疗，对运动前症状的评估将是必不可少的 考虑到未来的情况。由于这项申请的预算限制和我们的初步数据 我们提出了一项有针对性的临床研究，表明女性患FXTAS的风险显著降低。 只对男性进行研究，但强调这一项目将作为未来研究的跳板。 这个项目的总体目标是测试假说，这些假说将提供对病理学和 FXTAS的病程，以便：1)指定神经保护干预的时间点；2)提供 FXTAS相关症状的循证治疗策略。由于预算的限制，我们有 开发了一个小型的、专注的临床研究项目，主要检查非运动症状和他们的 进展，利用我们目前的研究样本。然而，我们设想这个项目是一个试点项目。 这可以在脆弱X中心的结构内得到加强，该中心扩展了目前正在进行的 埃默里和贝勒的项目解决了脆性X相关疾病。例如，我们的研究队列表明 已经使用当前脆弱X中心赠款的资金进行了仔细的表型鉴定将在未来可用 基于彭博士令人兴奋的数据检查FXTAS的遗传和环境修饰因素的研究 金的实验室。金博士是我们部门的一名年轻的研究员，他对 对前突变信使核糖核酸毒性效应的理解(例如，段和金，2006；例如，金等人，2003； Yang等人，2007)。我们的计划是使用从这项拟议的初步研究和从其他 我们机构内的合作者衍生出具有相同基本目标的新项目，以改善 FXTAS的症状。与此同时，我们已经走出了我们脆弱的X中心“墙”，并建立了一个 FXTAS工作组和其他从事FXTAS工作的调查人员。我们的目标是建立表型 记录疾病过程的方法是便携的，可以在正在进行的研究中共享 在多个地点进行。这种数据共享将是未来临床和翻译的重要组成部分 FXTAS的研究。