The Role of FBN1 in mammalian energy balance

FBN1 在哺乳动物能量平衡中的作用

• 批准号: 8749093
• 负责人: Atul Chopra
• 金额: $ 14.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8749093
• 关键词: Accounting; Adipocytes; Adipose tissue; Advisory Committees; Affect; Age; Alleles; Amino Acids; Basic Science; Biology; Board Certification; Body Composition; C-terminal; Cells; Clinical; Comorbidity; Consumption; DNA copy number; Dermal; Development; Development Plans; Diabetes Mellitus; Disease; Distal; Doctor of Medicine; Doctor of Philosophy; Dominant Genes; Dominant-Negative Mutation; Educational workshop; Electron Microscopy; Employee Strikes; Energy Intake; Environment; Equation; Exons; Extracellular Matrix Proteins; FBN1; Fibroblasts; Figs - dietary; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genus Hippocampus; Goals; Grant; Hereditary Disease; Homeostasis; In Vitro; International; Journals; Laboratories; Lead; Learning; Lipodystrophy; Literature; Marfan Syndrome; Measurement; Medical Genetics; Mentors; Messenger RNA; Metabolic; Metabolic syndrome; Mitochondria; Mitochondrial DNA; Molecular; Morbid Obesity; Morphology; Mutation; Obesity; Organ; Outcome; Oxygen Consumption; Patients; Phenotype; Physical activity; Play; Process; Proteins; Rare Diseases; Relative (related person); Research; Research Personnel; Research Technics; Research Training; Respiration; Role; Scientist; Site; Steatorrhea; Technology; Testing; Thinness; Training; Weight; Writing; base; bench to bedside; career; career development; cell type; clinically relevant; design; energy balance; exome sequencing; experience; extracellular; gain of function; genome-wide; in vivo; insight; medical specialties; meetings; mutant; new therapeutic target; overexpression; patient oriented research; polypeptide; programs; public health relevance; research study; selective expression; subcutaneous

DESCRIPTION (provided by applicant): The proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic career in clinically-relevant basic science. The applicant holds M.D. and Ph.D. degrees, and is completing specialty training, leading to board certification, in Medical Genetics. The career development plan includes mentored research training which will comprise learning new research techniques and concepts supplemented by didactic training, seminars, grant-writing workshops, lab meetings, journal clubs, presentations at national/international meetings, an advisory committee and regular meetings with the mentors. The research environment provides the best intellectual environment and technology available and gives the applicant the opportunity to be guided in learning adipose and mitochondrial biology and patient oriented research. The research seeks to take insights provided by patients suffering from a rare genetic disease that leads to extreme thinness into the laboratory in order to unravel the mechanism by which such a phenotype is produced. In that, it is an example of bedside- to-bench basic science that has the potential to inform far commoner diseases such as obesity, metabolic syndrome and diabetes. The patients have all been identified to have distal, heterozygous, truncating mutations in FBN1, which encodes for Fibrillin-1, an extracellular matrix protein that is associated with Marfan syndrome. The patients have much greater than normal caloric intake, and there is no evidence of excessive physical activity or steatorrhea, suggesting enhanced mitochondrial uncoupling as a means for loss of energy. FBN1 is expressed highly in white adipose tissue and its expression changes robustly upon manipulation of fat cells in vitro and in vivo. Adipose tissue derived from C-terminal truncation mutant fibroblasts, compared with WT, displays a gene expression profile consistent with turning off of the white adipose program in favor of the brown/beige adipose program, including a large increase in UCP1, which is a marker of uncoupled respiration. This provides a plausible avenue for unabated energy loss potentially leading to extreme thinness. The proposed research will define the mitochondrial phenotype of C-terminal truncation mutant fibroblasts and derived adipocytes, and will test the predicted increased metabolic rate in affected patients. The mechanistic basis for this phenotype will then be explored by defining the mRNA and protein product of the mutant allele followed by establishing whether haploinsufficiency of the missing polypeptide or dominant negative/neomorphic effect of the mutant protein is responsible for the effect. This research will create a broader understanding of the development of white and beige adipose tissue and associated mitochondrial biology. This could have clinical implications, and has the potential to provide new therapeutic targets, against obesity, metabolic syndrome and other highly prevalent comorbidities associated with energy excess. This research will occur in an environment dedicated to training the applicant to pursue this research further as an independent scientist.

描述(由申请人提供)：该提案描述了一项为期五年的有指导的实验室培训经验，旨在引导您在与临床相关的基础科学领域取得独立的学术生涯。申请人拥有医学博士和博士学位，并正在完成医学遗传学的专业培训，从而获得董事会认证。职业发展计划包括有指导的研究培训，这将包括学习新的研究技术和概念，并辅之以教学培训、研讨会、赠款编写讲习班、实验室会议、期刊俱乐部、在国家/国际会议上的陈述、咨询委员会和与导师的定期会议。研究环境提供了最好的智力环境和可用的技术，并使申请者有机会在学习脂肪和线粒体生物学以及以患者为导向的研究方面得到指导。这项研究试图将患有一种罕见遗传病的患者提供的见解带入实验室，以揭开这种表型产生的机制。在这一点上，它是一个从床边到工作台的基础科学的例子，有可能为肥胖、代谢综合征和糖尿病等更常见的疾病提供信息。这些患者都已被确认在FBN1基因上存在远端杂合性截断突变，FBN1编码纤维蛋白-1，一种与马凡综合征相关的细胞外基质蛋白。患者的卡路里摄入量远远高于正常，没有证据表明过度的体力活动或脂肪泻，表明加强线粒体解偶联是一种能量损失的手段。FBN1在白色脂肪组织中高表达，在体内外脂肪细胞作用下，其表达发生显著变化。与WT相比，来自C末端截断突变成纤维细胞的脂肪组织显示出与关闭白色脂肪程序而支持棕色/米色脂肪程序一致的基因表达谱，包括作为非偶联呼吸标志的UCP1的大幅增加。这为有增无减的能量损失提供了一条看似合理的途径，可能会导致极端瘦身。这项拟议的研究将确定C末端截断突变的成纤维细胞和衍生脂肪细胞的线粒体表型，并将测试受影响患者中预计的代谢率增加。然后将通过定义突变等位基因的mRNA和蛋白质产物来探索这种表型的机制基础，然后确定是缺失多肽的单倍体不足还是突变蛋白的显性负/新效应导致了这种效应。这项研究将使人们对白色和米色脂肪组织的发育以及相关的线粒体生物学有更广泛的了解。这可能具有临床意义，并有可能提供新的治疗靶点，以对抗肥胖、代谢综合征和其他与能量过剩相关的高度普遍的共病。这项研究将在一个致力于培训申请者作为独立科学家进一步开展这项研究的环境中进行。