Making sense of sequence - high throughput experiments in human adipocytes

描述(申请人提供)：Majithia博士的目标是阐明疾病机制并确定2型糖尿病(T2D)的治疗目标。为了实现这一长期目标，该提案详细介绍了一项为期五年的全面培训计划，以指导分子内分泌学的职业发展，使他能够过渡为一名独立的研究人员。马吉西亚博士在马萨诸塞州总医院完成了内分泌学、糖尿病和新陈代谢方面的临床培训。为了开发一个独立的研究计划，专注于阐明T2D的分子机制，他提出了一个教学和实践研究培训课程，以成熟结合人类遗传学、基于细胞的实验和临床表型的研究方法。为此，他建立了MGH/布罗德研究所人类遗传学和基因组解释的先驱David Altshuler和哈佛医学院国际公认的脂肪细胞生物学家Evan Rosen之间的联合导师关系。此外，他还组建了一个多元化的国际科学咨询委员会，成员包括胰岛素抵抗、人类核激素受体突变和分子内分泌学领域的杰出科学家哈维·洛迪什、克里希纳·查特吉和亨利·克罗南伯格。这些在遗传学、细胞科学和临床表型鉴定方面拥有不同专业知识的导师和顾问共同组成了一个理想的团队，以促进马吉蒂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PPARG中所有可能的突变的功能，PPARG是T2D治疗的重要药物靶点；2)量化PPARG突变、蛋白质功能和T2D风险之间的关系；3)证明这些方法在PPARG之外的普遍适用性。为了实现这些目标，马吉西亚博士将利用他导师实验室测序的基因组和数千人的临床数据所提供的独特资源。这项建议的研究目标将使马吉西亚博士能够提高基因组规模数据分析的技能，开发人们普遍感兴趣的新的高通量实验方法，并展示这些方法在解释人类测序数据方面的应用。总的来说，从拟议的实验和结构化的职业发展计划中获得的经验将为Majithia博士的R01建议和他向独立临床医生兼研究员的过渡奠定坚实的基础。

DESCRIPTION (provided by applicant):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.