Making sense of sequence - high throughput experiments in human adipocytes

项目摘要/摘要 Majithia博士的目标是阐明2型糖尿病的发病机制并确定治疗目标 (T2D)。为了实现这一长期目标，这项建议详细说明了一项全面的五年培训计划 指导他在分子内分泌学方面的职业发展，使他能够过渡为独立的 调查员。Majithia博士已完成内分泌学、糖尿病和新陈代谢方面的临床培训 麻省总医院。开发一个独立的研究项目，专注于阐明 对于T2D的分子机制，他提出了一个讲授和动手研究培训的课程，以成熟和 结合人类遗传学、细胞实验和临床表型的研究方法。至 为此，他建立了人类遗传学先驱大卫·阿尔特舒勒和 MGH/布罗德研究所的基因组解释，以及国际公认的脂肪细胞Evan Rosen 哈佛医学院的生物学家。此外，他还汇集了一个多元化的、国际化的科学 咨询委员会由Harvey Loish、Krishna Chatterjee和Henry Kronenberg组成 胰岛素抵抗、人类核激素受体突变和分子生物学领域的科学家 内分泌学。这些导师和顾问共同拥有不同领域的遗传学、基于细胞的专业知识 科学和临床表型分析组成了一个理想的团队，以促进马吉西亚博士自己的多学科方法。 这项拟议的研究旨在1)应用一种新的、基于实验的方法来解释所有 T2D治疗的重要药物靶点PPARG可能发生突变；2)量化 PPARG突变、蛋白质功能和T2D风险；3)展示这些方法的普遍适用性 超越PPARG。为了实现这些目标，马吉蒂亚博士将利用通过他的 Mentor的实验室测序了数千人的基因组和临床数据。的研究目标是 这项建议将使马吉西亚博士能够提高基因组规模数据分析的技能，开发出新的、高效率的 一般感兴趣的吞吐量实验方法，并演示这些方法在 人类测序数据的解释。总的来说，从拟议的实验中获得的经验 和结构化的职业发展计划将成为Majithia博士R01提案的坚实基础 以及他向独立临床医生兼调查员的转变。

PROJECT SUMMARY/ ABSTRACT Dr. Majithia's goal is to elucidate mechanisms of disease and identify therapeutic targets for Type 2 Diabetes (T2D). To achieve this long-term goal, this proposal details a comprehensive five-year training program for mentored career development in molecular endocrinology to enable his transition as an independent investigator. Dr. Majithia has completed clinical training in endocrinology, diabetes and metabolism at the Massachusetts General Hospital. To develop an independent research program focused on elucidating molecular mechanisms for T2D, he proposes a course of didactic and hands-on research training to mature an investigative approach combining human genetics, cell-based experimentation, and clinical phenotypes. To this end, the he has established a joint mentorship between David Altshuler, a pioneer in human genetics and genome interpretation at the MGH/Broad Institute, and Evan Rosen, an internationally recognized adipocyte biologist at Harvard Medical School. Additionally, he has assembled a diverse and international scientific advisory committee consisting of Harvey Lodish, Krishna Chatterjee, and Henry Kronenberg, luminary scientists in the fields of insulin resistance, nuclear hormone receptor mutations in humans, and molecular endocrinology. Together, these mentors and advisors with diverse fields of expertise in genetics, cell-based science and clinical phenotyping form an ideal team to foster Dr. Majithia's own multi-disciplinary approach. The proposed research aims to 1) apply a novel, experimentally based method to interpret the function of all possible mutations in PPARG, an important drug target for T2D treatment; 2) quantify the relationship between PPARG mutations, protein function, and T2D risk; 3) demonstrate general applicability of these methods beyond PPARG. To accomplish these aims, Dr. Majithia will leverage a unique resource available through his mentor's laboratory-sequenced genomes and clinical data on thousands of individuals. The research aims of this proposal will enable Dr. Majithia to advance skills in genome scale data analysis, develop novel, high- throughput experimental methods of general interest, and demonstrate application of these methods to the interpretation of human sequencing data. Collectively, the experience gained from the proposed experiments and structured career development plan will serve as a strong foundation for the Dr. Majithia's R01 proposal and his transition to an independent clinician-investigator.