FXTAS Key Molecular Pathways Converge with Other Neurodegenerative Disorders

项目总结/摘要 候选人。Lozano博士是一位早期的职业医生科学家，他利用自己的学术 在临床和基础科学的成就和多样化的培训，以发展独立的研究计划。 通过他的工作，他发展了遗传学和分子生物学以及临床实验室技能。 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。Lozano博士的总体长期职业目标是领导一个有意义的和可持续的 研究计划，这将使他仍然是一个完善的和独立的调查员在该地区的 脆性X相关疾病。这些目标将通过加强指导来实现（艾莉森·高特博士 （导师）、张斌（共同导师）和乔治迪亚兹（共同导师）），有意义的合作，以及个性化的 教学机制，这在本申请中概述。 体制环境。伊坎学院遗传学与基因组科学系 医学在西奈山是一个混合世界级的基础科学和临床计划，提供了一个广泛的基础 教学，研究和临床服务计划。教师是分子应用方面的专家 生物学、数据科学和用于遗传疾病研究的体细胞方法。环境 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 明白 的 假设 的 在 RNA 转录组 机制， 到 与 硬化症/额颞叶 FXTAS 确定 目前还没有有效的治疗神经退行性疾病（NDD）的方法。 为了开发潜在的治疗靶点， 脆性X相关震颤/共济失调综合征（FXTAS）提供了一个机会， NDD病症的病理机制，其源于确定的遗传病因学。整体 蛋白质清除缺陷会因多肽和mRNA-FMR 1而加剧， CGG扩展。这导致神经元反应驱动的泛素蛋白的增加， 包涵体，导致细胞功能障碍，反应性炎症小胶质细胞，最终神经变性 将使用测序（批量和单个核）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的生物学 将采用无偏见和无假设的方法来发现关键的分子途径。 为了识别NDDS中的收敛病理过程，将对新的FXTAS数据集进行交叉检查 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确定驱动 发病机制，这将有助于发现生物标志物和治疗靶点，但也 通过与其他NDD的交叉检查方法，研究疾病最核心的途径。 得双曲余切值. 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