Novel pathways in C9ORF72-associated ALS and dementia

C9ORF72 相关 ALS 和痴呆的新途径

基本信息

批准号：
10642695
负责人：
Daniel Adam Mordes
金额：
$ 19.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642695
关键词：
ADP ribosylation Acceleration Affect Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Animal Model Arginine Award Behavior Biological Models Brain C9ORF72 CRISPR/Cas technology Cell physiology Cerebrospinal Fluid Characteristics Chemicals Clinical Clinical Trials Computer Analysis Data Dementia Development Development Plans Dipeptides Disease Disease Progression Doctor of Philosophy Drug usage Environment Enzymes Fostering Frontotemporal Dementia Gene Expression General Hospitals Genes Genetic Genetic Screening Genetic Transcription Goals Histologic Human Impaired cognition Institution Introns K-Series Research Career Programs Laboratories Laboratory Research Language Massachusetts Mediating Mediator Mentors Methods Modeling Motor Motor Cortex Motor Neurons Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurological Models Neuromuscular Diseases Neurons Nuclear Paralysed Parkinson Disease Pathogenesis Pathologic Pathway interactions Patient Selection Personality Phenocopy Physicians Pluripotent Stem Cells Polymerase Production Proteins Proteomics Protocols documentation Publishing Research Research Personnel Research Proposals Resources Role Scientist Signal Pathway System Therapeutic Toxic effect Training Training Programs Translating Translational Research Universities Work Yeasts alpha synuclein cancer therapy career development clinical training design fly frontotemporal lobar dementia amyotrophic lateral sclerosis genome editing human stem cells improved inhibitor insight instructor medical schools meetings nervous system disorder neuropathology neuroprotection novel novel therapeutic intervention patient population polyglycine professor programs response senior faculty skills small molecule stem cell biology stem cell differentiation stem cells symposium therapeutic candidate therapeutic development therapeutic target transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract This is an application for the Mentored Clinical Scientist Career Development Award (K08) for Dr. Daniel Mordes, an Instructor at Massachusetts General Hospital, Harvard Medical School. This proposal describes a 5-year training program comprised of mentored laboratory research, formal coursework, seminars, and conferences to foster the career development of an academic physician-scientist in the subspecialty of neuropathology. This award will provide the necessary support to establish Dr. Mordes as an independent investigator studying frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). He aims to 1) master current methods using stem cells to model neurological disease, 2) obtain the executive skills to manage an independent translational research laboratory 3) become an expert in the neuropathology of neurodegenerative disease. In order to accomplish these goals, Dr. Mordes has designed a career development plan and assembled a group of accomplished basic scientists and physician- scientists with expertise in stem cell biology, cellular signaling pathways, neurobiology, genome editing, and neurodegenerative disease. The Applicant: Dr. Mordes graduated AOA from the MD/PhD program at Vanderbilt University and has completed clinical training in Neuropathology at Massachusetts General Hospital (MGH). Institutional Environment and Mentor: The training program combines the unique clinical and research resources of MGH with the laboratory of Professor Kevin Eggan, who has a strong track record of mentoring successful independent investigators, at Harvard University. Career Development Plan: Dr. Mordes has assembled a team of senior faculty advisors at MGH and Harvard Medical School to support his career development. His training will include the completion of advanced coursework and technical training at Harvard, HMS, and the Broad Institute, and the presentation of his research at national meetings. Research: Frontotemporal dementia (FTD) is a devastating neurodegenerative disease characterized by severe cognitive impairments and the progressive loss of cortical neurons. There are no disease-modifying treatments approved for FTD. Forms of FTD have shared neuropathological features with amyotrophic lateral sclerosis (ALS), which is a rapidly progressive neuromuscular disorder. The most common genetic cause of ALS and FTD is a hexanucleotide repeat expansion in C9ORF72, which is associated with the production of toxic dipeptide repeat proteins (DPRs). Dr. Mordes has employed new methods of producing human neurons from pluripotent stem cells to establish models of C9ORF72-associated disease. He aims to understand the effects of DPRs in specific neuronal types through a combination of transcriptomics, proteomics, and neuropathological approaches, and to identify novel cellular pathways for the development of candidate treatments. Furthermore, he will determine the effects of a specific nuclear signaling pathway on the neuronal response to DPRs. This research will improve our understanding of ALS and FTD and will help guide the establishment of new, and urgently needed, therapeutic efforts aimed at slowing disease progression.

项目摘要/摘要这是指导的临床科学家职业发展奖（K08）的申请哈佛医学院马萨诸塞州综合医院的讲师Daniel Mordes博士。这提案描述了一项为期5年的培训计划，该计划由受过指导的实验室研究，正式研究组成课程，研讨会和会议，以促进学术医师科学家的职业发展在神经病理学的亚科中。该奖项将为建立博士提供必要的支持。作为研究额颞痴呆（FTD）和肌萎缩性侧面的独立研究者硬化症（ALS）。他的目的是1）使用干细胞对神经系统疾病进行建模的掌握当前方法，2）获得管理独立翻译研究实验室的执行技能3）成为专家在神经退行性疾病的神经病理学中。为了实现这些目标，Mordes博士有设计了一项职业发展计划，并组建了一群成熟的基础科学家和医师 - 具有干细胞生物学，细胞信号通路，神经生物学，基因组编辑的专业知识的科学家，和神经退行性疾病。申请人：Mordes博士从MD/PHD计划毕业范德比尔特大学（Vanderbilt University）已完成马萨诸塞州神经病理学的临床培训医院（MGH）。机构环境和导师：培训计划结合了独特的临床以及MGH的研究资源与凯文·埃格甘（Kevin Eggan）的实验室，他的往绩很强在哈佛大学指导成功的独立研究人员。职业发展计划：博士 Mordes已在MGH和哈佛医学院组建了一支高级教师顾问团队，以支持他的职业发展。他的培训将包括完成高级课程和技术在哈佛，HMS和Broad Institute的培训，以及他在国家会议上的研究。研究：额颞痴呆（FTD）是一种毁灭性神经退行性疾病，其为特征严重的认知障碍和皮质神经元的逐渐丧失。没有疾病调整批准FTD的治疗。 FTD的形式具有肌萎缩症的神经病理学特征横向硬化症（ALS），这是一种快速进行性神经肌肉疾病。最常见的遗传 ALS和FTD的原因是C9orf72中的六核苷酸重复扩展，与产生有毒二肽重复蛋白（DPRS）。 Mordes博士采用了新的生产方法来自多能干细胞的人类神经元以建立与C9ORF72相关疾病的模型。他的目标通过结合转录组学的组合，了解DPR在特定神经元类型中的影响，蛋白质组学和神经病理学方法，并确定新的细胞途径候选治疗。此外，他将确定特定的核信号通路的影响关于对DPRS的神经元反应。这项研究将提高我们对ALS和FTD的理解，并将帮助指导建立旨在减慢疾病的新的，急需的治疗努力进展。