Making sense of sequence - high throughput experiments in human adipocytes

理解序列——人类脂肪细胞的高通量实验

• 批准号: 8915689
• 负责人: Amit Majithia
• 金额: $ 13.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915689
• 关键词: Adipocytes; Adipose tissue; Advisory Committees; Affect; American; Amino Acid Substitution; Benign; Biological Assay; Biological Models; Biological Process; Cell model; Cells; Cellular Assay; Classification; Clinical; Clinical Data; Data; Data Analyses; Data Set; Development Plans; Diabetes Mellitus; Disease; Drug Targeting; Endocrinologist; Endocrinology; Engineering; Environmental Risk Factor; Epidemic; Evaluation; Fluorescence-Activated Cell Sorting; Fostering; Foundations; Functional disorder; Future; General Hospitals; General Population; Genes; Genetic; Genome; Genotype; Goals; Gold; Health; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Human Genetics; Human Genome; Individual; Inherited; Institutes; Insulin Resistance; International; Joints; Laboratories; Lamin Type A; Libraries; Link; Lipodystrophy; Massachusetts; Measures; Mediating; Mentors; Mentorship; Metabolic; Metabolism; Methods; Molecular; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; PPARG gene; Phenotype; Physiological; Play; Positioning Attribute; Proteins; Research; Research Personnel; Research Training; Resources; Risk; Role; Science; Scientist; Sorting - Cell Movement; Statistical Methods; Structure; System; Testing; Tissue Expansion; Training; Training Programs; Variant; Work; adipocyte differentiation; base; career; career development; case control; cell type; clinical phenotype; cohort; diabetes risk; exome sequencing; experience; genetic risk factor; genetic variant; genome sequencing; genome-wide; human disease; interest; loss of function; medical schools; next generation sequencing; novel; programs; prospective; protein function; rare variant; research study; screening; skills; therapeutic target

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.

描述（由申请人提供）：Majithia博士的目标是阐明疾病机制并确定2型糖尿病（T2 D）的治疗靶点。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，使他能够过渡为独立研究者。Majithia博士在马萨诸塞州总医院完成了内分泌学、糖尿病和代谢方面的临床培训。为了开发一个专注于阐明T2 D分子机制的独立研究计划，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，他在MGH/Broad研究所的人类遗传学和基因组解释先驱大卫阿尔特什基和哈佛医学院国际公认的脂肪细胞生物学家埃文罗森之间建立了联合导师关系。此外，他还组建了一个多元化的国际科学咨询委员会，由Harvey Lodish，Krishna Chatterjee和亨利克罗嫩伯格组成，他们是胰岛素抵抗，人类核激素受体突变和分子内分泌学领域的杰出科学家。这些导师和顾问在遗传学、细胞科学和临床表型方面具有不同的专业知识，他们共同组成了一个理想的团队，以培养Majithia博士自己的多学科方法。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中所有可能突变的功能，PPARG是T2 D治疗的重要药物靶点; 2）量化PPARG突变，蛋白质功能和T2 D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，Majithia博士将利用他的导师的实验室测序基因组和数千人的临床数据提供的独特资源。该提案的研究目标将使Majithia博士能够提高基因组规模数据分析的技能，开发普遍感兴趣的新型高通量实验方法，并展示这些方法在人类测序数据解释中的应用。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R 01提案及其向独立临床研究者的过渡奠定坚实的基础。