FXTAS Key Molecular Pathways Converge with Other Neurodegenerative Disorders

项目摘要/摘要 候选人。洛扎诺博士是一位职业生涯早期的内科医生兼科学家，他利用自己的学术 在临床和基础科学方面的成就和多样化的培训，以制定独立的研究计划。 通过他的工作，他培养了遗传学和分子生物学以及临床方面的实验室技能。 这些研究共同构成了这个正在进行的项目的基础。 职业发展。洛扎诺博士的总体长期职业目标是领导一个有意义和可持续的 研究计划，将使他保持在该领域的成熟和独立的调查员 脆性X相关疾病。这些目标将通过紧张的指导来实现(艾莉森·戈特博士 (导师)、张斌(共同导师)和George Diaz(共同导师))、有意义的协作和个性化 说教机制，在本申请中概述。 制度环境。伊坎大学遗传学与基因组科学系 西奈山医学是一个世界级的基础科学和临床混合项目，提供广泛的基础 教学、研究和临床服务计划。这些教师都是分子应用方面的专家。 研究遗传病的生物学、数据科学和体细胞方法。环境问题 在该部门提供的是执行本申请中概述的研究的理想选择。 研究项目。那里 在……里面 明白了。 这个 假设 这个 在……里面 核糖核酸 转录组 机械装置， 至 使用 硬化症/额颞部 FXTAS 确定 目前还没有有效的治疗神经退行性疾病(NDDS)的方法。 为了开发潜在的治疗靶点，潜在的生物学机制必须更加清楚 脆性X相关震颤/共济失调综合征(FXTAS)为深入了解 NDD疾病的病理机制源于明确的遗传病因学。整体而言 是蛋白质清除缺陷被多肽和产生的mRNA-FMR1加剧 CGG扩展。这会导致神经元反应导致沉积的泛素蛋白增加。 包涵体，导致细胞功能障碍，反应性炎性小胶质细胞，最终导致神经变性 测序(散装和单核)将用于定性和定量检查 在死后的人体组织中。由于NDD涉及复杂和相互交织生物 将应用一种无偏见和无假设的方法来发现关键的分子途径。 确定NDDS中收敛的病理L过程，新的FXTAS数据集将被交叉检查 阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的可用数据集 痴呆症。这项研究不仅有可能识别关键的驱动机制 致病机制将促进发现生物标志物和治疗靶点，但也 通过与其他非脱氧核糖核酸交叉询问的方法，确定对疾病最重要的途径。 ，t O 。 D S F

PROJECT SUMMARY/ABSTRACT THE CANDIDATE. Dr. Lozano is an early career physician-scientist, who has drawn on his academic achievement and diverse training in clinical and basic science to develop an independent research program. Through his work, he has developed laboratory skills in genetics and molecular biology, as well as clinical research which together form the foundations of this ongoing project. CAREER DEVELOPMENT. Dr. Lozano's overall long-term career goal is to lead a meaningful and sustainable research program that will allow him to remain a well-established and independent investigator in the area of Fragile X-related disorders. These goals will be accomplished through intense mentorship (Drs. Alison Goate (mentor), Bin Zhang (co-mentor), and George Diaz(co-mentor)), meaningful collaborations, and personalized didactic mechanisms, which are outlined in this application. INSTITUTIONAL ENVIRONMENT. The Department of Genetics & Genomic Sciences at the Icahn School of Medicine at Mount Sinai is a hybrid world-class basic science and clinical program that offers a broad-based program of instruction, research, and clinical services. The faculty are experts in the application of molecular biology, data science, and somatic cell approaches for the study of genetic diseases. The environment provided in the department is ideal for the execution of the studies outlined in this application. RESEARCH PROJECT. There In understood. the hypothesis the in RNA transcriptome mechanisms, To with sclerosis/Frontotemporal FXTAS determine are currently no effective treatments for neurodegenerative disorders (NDDs). order to develop potential therapeutic targets the underlying biological mechanisms mus be more clearly Fragile X-associated tremor/ataxia syndrome (FXTAS) ffers an opportunity to gain insights into pathological mechanisms for an NDD disorder that stems from a defined genetic etiology. The overall is that protein clearance deficits are exacerbated by polypeptides and mRNA-FMR1 produced from CGG expansion. This results in neuronal response-driven increases in ubiquitin proteins that are deposited inclusions, leading to cell dysfuction, reactive inflammatory microglial and eventually neurodegeneration sequencing (bulk and single nuclei) will be used to qualitatively and quantitatively examine the in postmortem human tissue. Since NDDs involve complex and intertwined biological an unbiased and hypothesis-free approach for key molecular pathways discovery will be applied. identify the converging pathologica l processes in NDDS, the novel FXTAS datasets will be cross-examined available datasets of Alzheimer's Disease, Parkinson Disease and amyotrophic lateral ementia . This tudy has the potential to not only identify critical mechanisms driving pathogenesis that would acilitate the discovery of biomarkers and therapeutic targets but also pathways most central to disease through a cross-examination approach with other NDDs. , t o . d s f