Research Mentoring in Neurology and Translational Research on Alzheimers Disease

 描述(申请人提供)：这份K24申请满足了迫切的公共卫生需求，以发展一条年轻科学家的管道，从事神经疾病的翻译研究，并更好地了解家族性阿尔茨海默病(FAD)的发病机制和表型。这项建议的双重目标是：(1)建立一个创新的跨学科指导计划，专注于加强麻省总医院(MGH)神经内科研究员和早期初级教员的研究、培训和职业发展；(2)通过获取涉及产生和多学科分析具有人类FAD患者特有PSEN1突变的诱导多能干细胞衍生神经元的新方法，扩大PI针对AD的翻译研究的患者导向部分。K24奖将是允许PI通过提供保护时间来实现这些目标的关键，以避免日益增长的临床和行政负担。拟议的指导计划建立在PI作为临床科学家和导师的丰富经验的基础上，强调翻译神经科学方面的跨学科教育、培训和指导。该计划基于PI对初级研究人员需求的评估，并坚信大脑疾病的复杂性将越来越需要利用基础神经科学、遗传学和基因组学以及干细胞技术的进步的跨学科方法。指导计划得益于麻省理工学院神经病学系的优势，以及与麻省理工学院、哈佛大学和麻省理工学院其他高度相关的部门和中心的合作联盟。具体组成部分包括教师导师的跨学科网络；关于遗传学、基因组学和细胞重新编程技术的最新课程；提高拨款撰写技能的研讨会；研究员和初级教师非正式介绍研究想法和结果的系列研讨会；以及将博士科学家纳入住院临床团队。这些辅导工作的成功 将通过具体的指标进行跟踪，包括拨款提交和成功率、参加研讨会、课程和研讨会的人数以及内部调查。拟议的研究计划建立在PI在细胞培养和小鼠模型系统中FAD的机制研究方面的丰富经验的基础上，并试图将PI产生和分析新型早老素-1敲入小鼠的有趣的最新发现转化为人类FAD患者。为了实现这些目标，PI将在人类IPSC来源的神经元的生成和功能基因组分析方面获得新的专业知识，并将其应用于多种FAD相关表型的分析。这些技术的获取和实施将由一组专家合作者提供便利。这些研究有可能为FAD的发病机制提供新的见解，可能揭示新的靶向途径和治疗开发途径。

 DESCRIPTION (provided by applicant): This K24 application addresses urgent public health needs to develop a pipeline of young scientists pursuing translational research on neurologic disorders, and to develop a better understanding of pathogenic mechanisms and phenotypes in familial Alzheimer's disease (FAD). The dual goals of this proposal are: (1) to establish an innovative interdisciplinary mentoring program focused on enhancing the research training and career development of fellows and early-stage junior faculty in the Department of Neurology at the Massachusetts General Hospital (MGH); and (2) to expand the patient-oriented component of the PI's translational research on AD through the acquisition of new approaches involving generation and multidisciplinary analysis of induced pluripotent stem cell-derived neurons bearing human FAD patient-specific PSEN1 mutations. The K24 award will be critical in allowing the PI to realize these goals by providing protected time from growing clinical and administrative burdens. The proposed mentoring program, which builds on the PI's substantial experience as a clinician-scientist and mentor, emphasizes interdisciplinary education, training, and mentoring in translational neuroscience. The program is based on the PI's assessment of the needs of junior researchers and the conviction that the complexity of brain disorders will increasingly require interdisciplinary approaches that take advantage of advances in basic neuroscience, genetics and genomics, and stem cell technologies. The mentoring program benefits from the strengths of the MGH Neurology Department and collaborative alliances with other highly relevant departments and centers at MGH, Harvard, and MIT. Specific components include an interdisciplinary network of faculty mentors; state-of-the-art courses on genetics, genomics and cellular reprogramming technologies; workshops to enhance grant-writing skills; a seminar series for informal presentation of research ideas and results by fellows and junior faculty; and incorporation of Ph.D. scientists into inpatient clinical teams. Success of these mentoring efforts will be tracked by specific metrics including grant submission and success rates, attendance at workshops, courses, and seminars, and internal surveys. The proposed research program builds on the PI's extensive experience in mechanistic studies of FAD in cell culture and mouse models systems, and seeks to translate intriguing recent findings from the PI's generation and analysis of novel Presenilin-1 knock-in mice to human FAD patients. To accomplish these aims, the PI will acquire new expertise in generation and functional genomic analysis of human iPSC-derived neurons, which he will apply to analysis of multiple FAD-relevant phenotypes. Acquisition and implementation of these techniques will be facilitated by a team of expert collaborators. These studies have the potential to provide new insights into pathogenic mechanisms in FAD, potentially revealing novel target pathways and avenues for therapeutic development.