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: 9058075
• 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/9058075
• 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; Health; 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; 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; laboratory experience; medical specialties; meetings; metabolic rate; mutant; new therapeutic target; overexpression; patient oriented research; polypeptide; programs; research study; selective expression; subcutaneous; transcriptome sequencing

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）：该提案描述了一个为期五年的指导实验室培训经验，旨在导致在临床相关的基础科学的独立学术生涯。申请人持有医学博士学位。和博士学位，并正在完成专业培训，导致董事会认证，在医学遗传学。职业发展计划包括指导研究培训，其中包括学习新的研究技术和概念，辅以教学培训，研讨会，赠款写作研讨会，实验室会议，期刊俱乐部，在国家/国际会议上的演讲，咨询委员会和定期会议与导师。研究环境提供了最好的知识环境和技术，并为申请人提供了学习脂肪和线粒体生物学以及面向患者的研究的指导机会。该研究旨在将患有罕见遗传疾病的患者提供的见解带入实验室，以揭示产生这种表型的机制。在这方面，它是一个从床边到实验室的基础科学的例子，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。这些患者都被鉴定为FBN 1中有远端杂合截短突变，FBN 1编码Fibrillin-1，一种与马凡氏综合征相关的细胞外基质蛋白。患者的热量摄入量远高于正常，并且没有过度体力活动或脂肪过多的证据，表明增强的线粒体解偶联是能量损失的一种手段。FBN 1在白色脂肪组织中高度表达，并且其表达在体外和体内操作脂肪细胞时强烈变化。与WT相比，来源于C-末端截短突变体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UCP 1的大幅增加，UCP 1是解偶联呼吸的标志物。这提供了一个合理的途径，为有增无减的能量损失可能导致极端薄。拟议的研究将定义C-末端截短突变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的预测代谢率增加。然后通过定义突变等位基因的mRNA和蛋白质产物，然后确定缺失多肽的单倍不足或突变蛋白的显性负性/新变体效应是否是该效应的原因，来探索该表型的机制基础。这项研究将创造一个更广泛的理解发展的白色和米色脂肪组织和相关的线粒体生物学。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流行的合并症。这项研究将在一个致力于培训申请人作为独立科学家进一步从事这项研究的环境中进行。