Research Mentoring in Neurology and Translational Research on Alzheimers Disease

 描述（由申请人提供）：该K24申请解决了紧迫的公共卫生需求，以开发一个年轻科学家的管道，从事神经系统疾病的转化研究，并更好地了解家族性阿尔茨海默病（FAD）的致病机制和表型。该建议的双重目标是：（1）建立一个创新的跨学科指导计划，重点是加强马萨诸塞州总医院神经内科研究员和早期初级教师的研究培训和职业发展;（2）扩大病人的-通过收购涉及诱导多能干细胞生成和多学科分析的新方法，携带人FAD患者特异性PSEN 1突变的衍生神经元。K24奖将通过提供受保护的时间来避免日益增长的临床和管理负担，从而使PI实现这些目标。建议的指导计划，建立在PI的丰富经验，作为临床科学家和导师，强调跨学科的教育，培训和指导转化神经科学。该计划是基于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跨学科的方法，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。该指导计划受益于MGH神经病学部门的优势以及与MGH，哈佛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;遗传学，基因组学和细胞重编程技术的国家的最先进的课程;讲习班，以提高赠款写作技能;研讨会系列研究员和初级教师的研究思路和结果的非正式介绍;并纳入博士学位。将科学家纳入住院临床团队。这些辅导工作的成功 将通过具体指标进行跟踪，包括赠款提交和成功率，参加讲习班，课程和研讨会以及内部调查。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机制研究的广泛经验基础上，并寻求将PI对新型早老素-1基因敲入小鼠的生成和分析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将获得人类iPSC衍生神经元的生成和功能基因组分析方面的新专业知识，他将应用于多种FAD相关表型的分析。这些技术的获取和实施将由一个专家合作小组提供便利。这些研究有可能为FAD的致病机制提供新的见解，可能揭示新的靶向途径和治疗开发的途径。

 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.