Genetic investigations into adiponectin as a biologic mediator and a therapeutic

脂联素作为生物介质和治疗药物的遗传学研究

• 批准号: 8928732
• 负责人: Sujoy Ghosh
• 金额: $ 8.56万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928732
• 关键词: Address; Adipocytes; Adipose tissue; Adverse effects; African American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Asians; Biochemical; Biological Assay; Biology; Blood; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Cell Culture Techniques; Cellular Assay; Coupled; Data; Development; Disease; Epidemiology; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Health; Hormones; Insulin; Insulin Resistance; Investigation; Kidney; Knockout Mice; Libraries; Literature; Maps; Mediator of activation protein; Metabolic; Metabolic Diseases; Methods; Minority; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Output; Phenotype; Population; Procedures; Property; Quantitative Trait Loci; RNA; RNA Interference; Refractory; Regulator Genes; Reporting; Research; Resolution; Resources; Risk Reduction; Sampling; Signal Transduction; Single Nucleotide Polymorphism Map; System; Systems Biology; Testing; Therapeutic; Tissues; Translational Research; United States National Institutes of Health; Validation; Variant; adiponectin; base; cardiometabolic risk; disorder control; disorder risk; drug discovery; gene discovery; health disparity; human NOS3 protein; improved; in vitro Assay; insight; insulin sensitivity; mouse model; novel; screening; therapeutic target

Higher insulin resistance in African Americans has been suggested to disproportionately predispose this population to a host of cardio-metabolic disorders including obesity, type 2 diabetes and cardiovascular disease. We seek to transform this epidemiologic finding into the hypothesis that the inverse relationship between insulin resistance and the adipocyte-specific hormone, adiponectin, can be the basis for a novel treatment paradigm in cardio-metabolic disorders. A significant body of literature confirms the insulin-sensitizing, anti-inflammatory and cardioprotective properties of adiponectin. There is also substantial evidence of ethnic variation in adiponectin levels. More specifically, adiponectin levels are lower in African Americans and could partly explain the higher insulin resistance and attendant cardio-metabolic disease risk in this population. Polymorphisms in the adiponectin gene have been associated with adiponectin levels and insulin-sensitivity in Caucasian and Asian populations; however, there is a critical lack of comparable polymorphism mapping of adiponectin in African Americans. Also, despite the accumulation of certain mechanistic insights into adiponectin function, the full spectrum of adiponectin biology is yet to be elucidated through systems biology approaches. Finally, suitable in vitro assays for evaluating candidate adiponectin regulators identified from genetic and systems biology approaches are also lacking. To address these gaps, we propose translational research at the cellular, animal and population levels to critically evaluate adiponectin as a biologic mediator of, and a possible therapeutic target for, cardio-metabolic risk reduction. The unifying objective behind the proposed study is expansion of our understanding of adiponectin biology with reference to health disparities and development of key resources for enabling future investigations into adiponectin-modifying treatments. Since hypoadiponectinemia is frequently observed in African-Americans, our research carries added significance for addressing health disparities in minority populations.

非裔美国人的胰岛素抵抗更高，这被认为是不成比例的易感因素。 肥胖症、2型糖尿病和心血管疾病等一系列心脏代谢疾病的风险。 我们试图将这一流行病学的发现转化为这样一种假设，即胰岛素与胰岛素抵抗之间的负相关关系。 抵抗力和脂肪细胞特异性激素脂联素可以成为新型治疗范式的基础。 心脏代谢紊乱大量的文献证实了胰岛素增敏、抗炎和 脂联素的心脏保护特性。也有大量的证据表明脂联素的种族差异 程度.更具体地说，非裔美国人的脂联素水平较低，这可以部分解释非裔美国人的脂联素水平较高。 胰岛素抵抗和伴随的心脏代谢疾病风险。多态性 在高加索人和亚洲人中，脂联素基因与脂联素水平和胰岛素敏感性相关 然而，在非洲人群中，脂联素的多态性分布严重缺乏可比性。 美国人此外，尽管积累了一定的机制见解脂联素的功能， 脂联素生物学的谱尚待通过系统生物学方法阐明。最后，适合在 用于评价从遗传和系统生物学鉴定的候选脂联素调节剂的体外测定 方法也缺乏。为了解决这些差距，我们建议在细胞，动物 和人群水平，以严格评估脂联素作为生物介质和可能的治疗靶点 降低心脏代谢风险。拟议研究背后的统一目标是扩大我们的 了解脂联素生物学与健康差异和关键资源的开发， 使得未来能够研究脂联素修饰治疗。由于低脂联素血症经常 在非洲裔美国人中观察到，我们的研究对解决健康差距具有额外的意义， 少数民族人口。