Osteocalcin and Metabolic Risk Factors. The Framingham Study

骨钙素和代谢风险因素。

• 批准号: 7990841
• 负责人: Yi-Hsiang Hsu
• 金额: $ 20.93万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990841
• 关键词: Adipocytes; Affect; Animals; Arts; Bioinformatics; Biological; Blood Pressure; Candidate Disease Gene; Cell Proliferation; Cells; Central obesity; Communication; Computer Simulation; Data; Disease; Dyslipidemias; Endocrine; Energy Metabolism; Environment; Equation; Etiology; Fasting; Feedback; Framingham Heart Study; Funding; Future; Generations; Genes; Genetic; Genetic Determinism; Genotype; Heritability; High Density Lipoprotein Cholesterol; Homeostasis; Human; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Intake; Leptin; Link; Maps; Measures; Metabolic; Metabolic syndrome; Methods; MicroRNAs; Modeling; Molecular Target; NIH Program Announcements; Ontology; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Pancreas; Participant; Pathogenesis; Pathway interactions; Phenotype; Physical activity; Plasma; Play; Positioning Attribute; Production; Proteins; Regulation; Reporting; Research; Resources; Risk Factors; Rodent; Role; Sample Size; Sampling Studies; Science; Sequence Analysis; Serum; Signal Pathway; Skeleton; Structure; System; Testing; Time; Translating; Triglycerides; Vitamin D; Weight; Wild Type Mouse; Woman; Women' s Health; Work; adiponectin; analytical tool; base; blood glucose regulation; bone; bone cell; cardiovascular disorder risk; cohort; density; fasting plasma glucose; genetic pedigree; genetic variant; genome wide association study; genome-wide; glucose metabolism; high risk; human study; improved; indexing; insight; insulin secretion; insulin sensitivity; member; men; network models; novel; public health relevance; sex; tool; trait; waist circumference

DESCRIPTION (provided by applicant): Based on a recent discovery in rodents, for the first time, osteocalcin (OC), a major bone formation protein uniquely secreted by osteoblasts, may play a crucial role in endocrine regulation of energy metabolism by enhancing b-cell proliferation, insulin production, insulin sensitivity and adiponectin expression as a feedback loop of Leptin's regulation of osteoblasts. This new evidence suggests that bone cells not only function locally on the skeleton, but may also be involved in the pathogenesis of insulin resistance and the metabolic syndrome. However, the underlying mechanisms for how OC interacting with adipocytes, pancreatic 2 cells and other molecules functionally involved in glucose homeostasis are still unclear. The existence of biological evidence linking "endo-phenotypes" of often quite distinct diseases raises another possibility that diseases may not be as independent of each other as is often assumed. Our study attempts to link two systems: bone and energy metabolisms. Thus the underlying hypothesis of this proposal is that there are shared genetic variants that regulate both serum OC and metabolic risk factors (metabolic syndrome risk factor clustering: a combination of risk factors including central obesity, hyperglycemia, dyslipidemia, and hypertension). In this application we are proposing a genome-wide association (GWA) approach in the Framingham Heart Study to identify (1) novel genetic variants for serum OC and (2) shared genetic determinants with directly pleiotropic effects on both serum OC and metabolic risk factors (including waist circumference, systolic blood pressure, fasting triglycerides, fasting HDL cholesterol, fasting plasma glucose, fasting plasma insulin, adiponectin concentrations and insulin resistance indices such as HOMA-IR and QUICKI). The state-of-the-art GWA analytical approaches will be used including the multipe-phenotyping GWA analysis using a recent developed Principle of Heritability method, weighted hypotheses based on prior information, and a newly developed structure modeling to infer the directly pleotropic effects. Bioinformatics approaches, such as pathway network analyses, gene- set enrichment test, and eSNP analyses will also be applied. We will use already collected phenotype data and available high-density 550K Affymetrix genotyping data. The proposed work will take advantage of the rich available data and large sample size of the Framingham Heart Study. This will be the first human study using GWA approach to attempt to translate the OC findings from animals, which will afford the opportunity to generate new hypotheses to understand the signaling pathways and underlying biological mechanisms behind the crosstalk, as it is not fully understood how this bone protein regulates glucose metabolism, insulin secretion and insulin sensitivity. Confirmation of these findings in humans could also have important implications for women who commonly suffer from the morbid and sometimes mortal complications of both osteoporosis and cardiovascular disease risk factor clustering, metabolic syndrome. PUBLIC HEALTH RELEVANCE: Recent animal studies have showed that osteocalcin, an important bone protein, involves in the endocrine regulation of energy metabolism. However, the underlying mechanisms for how osteocalcin interacting with adipocytes and pancreatic 2 cells are still unclear. Our study will be the first human study using state-of-the-art genome-wide association approaches to attempt to identify novel genetic variants shared by both osteocalcin and metabolic risk factors, which will provide valuable insight into potential molecular targets that will help further understanding the underlying mechanisms of communication between skeleton and energy metabolism.

描述（申请人提供）：基于啮齿类动物的最新发现，骨钙素（OC）是一种由成骨细胞独特分泌的主要骨形成蛋白，它可能通过增强b细胞增殖、胰岛素产生、胰岛素敏感性和脂联素表达作为瘦素调节的反馈回路，在能量代谢的内分泌调节中发挥关键作用。 成骨细胞。这一新证据表明，骨细胞不仅在骨骼上发挥局部功能，还可能参与胰岛素抵抗和代谢综合征的发病机制。然而，OC 如何与脂肪细胞、胰腺 2 细胞和其他参与葡萄糖稳态功能的分子相互作用的潜在机制仍不清楚。将通常截然不同的疾病的“内表型”联系起来的生物学证据的存在提出了另一种可能性，即疾病可能不像通常假设的那样彼此独立。我们的研究试图将两个系统联系起来：骨骼和能量代谢。因此，该提议的基本假设是，存在调节血清OC和代谢危险因素（代谢综合征危险因素聚类：包括向心性肥胖、高血糖、血脂异常和高血压在内的危险因素的组合）的共同遗传变异。在本申请中，我们在弗雷明汉心脏研究中提出了全基因组关联 (GWA) 方法，以确定 (1) 血清 OC 的新遗传变异和 (2) 对血清 OC 和代谢危险因素（包括腰围、收缩压、空腹甘油三酯、空腹 HDL 胆固醇、空腹血糖、空腹血浆）具有直接多效性影响的共享遗传决定因素。 胰岛素、脂联素浓度和胰岛素抵抗指数（例如 HOMA-IR 和 QUICKI）。将使用最先进的 GWA 分析方法，包括使用最近开发的遗传性原理方法进行的多表型 GWA 分析、基于先验信息的加权假设以及新开发的结构模型来推断直接多效性。生物信息学方法，如通路网络分析、基因集富集测试和 eSNP 分析也将被应用。我们将使用已收集的表型数据和可用的高密度 550K Affymetrix 基因分型数据。拟议的工作将利用弗雷明汉心脏研究的丰富可用数据和大样本量。这将是第一个使用 GWA 方法尝试转化动物 OC 研究结果的人类研究，这将提供产生新假设的机会，以了解串扰背后的信号通路和潜在的生物学机制，因为目前尚不完全了解这种骨蛋白如何调节葡萄糖代谢、胰岛素分泌和胰岛素敏感性。这些研究结果在人类身上的证实也可能对经常患有骨质疏松症和心血管疾病危险因素聚集、代谢综合征等病态甚至致命并发症的女性产生重要影响。 公共健康相关性：最近的动物研究表明，骨钙素是一种重要的骨蛋白，参与能量代谢的内分泌调节。然而，骨钙素如何与脂肪细胞和胰腺2细胞相互作用的潜在机制仍不清楚。我们的研究将是第一个使用最先进的全基因组关联方法的人类研究，试图识别骨钙素和代谢危险因素共有的新遗传变异，这将为潜在的分子靶点提供有价值的见解，从而有助于进一步了解骨骼和能量代谢之间沟通的潜在机制。