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

基本信息

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
项目类别：
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

项目摘要

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）：DR。 Majithia的目标是阐明疾病的机制并确定2型糖尿病（T2D）的治疗靶标。为了实现这一长期目标，该提案详细介绍了一项全面的五年培训计划，用于指导分子内分泌学领域的职业发展，以使他成为独立研究者的过渡。 Majithia博士在马萨诸塞州综合医院完成了内分泌，糖尿病和代谢的临床培训。为了制定一项针对T2D的分子机制的独立研究计划，他提出了一种教学和动手研究培训的过程，以成熟的研究方法结合了人类遗传学，基于细胞的实验和临床表型。为此，他已经在MGH/Broad Institute的人类遗传学和基因组解释的先驱David Altshuler与哈佛医学院的国际认可的脂肪生物学家埃文·罗森（Evan Rosen）之间建立了共同的指导。此外，他组建了一个由Harvey Lodish，Krishna Chatterjee组成的多样化和国际科学咨询委员会，以及胰岛素抵抗，人类核激素受体突变领域的杰出科学家Henry Kronenberg和分子内分泌学领域。这些指导者和顾问共同拥有各种遗传学，基于细胞的科学和临床表型领域的专业知识领域，构成了Majithia博士自己的多学科方法的理想团队。拟议的研究目的是1）采用一种基于实验的新方法来解释PPARG中所有可能的突变的功能，PPARG是T2D处理的重要药物靶标； 2）量化PPARG突变，蛋白质功能和T2D风险之间的关系； 3）证明了这些方法以外的PPARG之外的一般适用性。为了实现这些目标，Majithia博士将利用通过其导师的实验室序列基因组和成千上万个人的临床数据获得的独特资源。该提案的研究目的将使Majithia博士能够提高基因组量表数据分析的技能，开发新颖的，高吞吐量的实验方法，并证明这些方法在解释人类测序数据的解释中的应用。总体而言，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提案以及他向独立的临床医生投票员的过渡提供强大的基础。