Molecular Epidemiology of the Wnt Pathway in Subclinical Cardiovascular Disease

亚临床心血管疾病 Wnt 通路的分子流行病学

• 批准号: 8965549
• 负责人: Allison L Kuipers
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965549
• 关键词: Abdomen; Address; African; Animal Model; Ankle; Area; Arteries; Arteriosclerosis; Atherosclerosis; Biological Assay; Biological Markers; Blood; Body Composition; Caliber; Cardiovascular Diseases; Cardiovascular Physiology; Carotid Arteries; Carotid Atherosclerotic Disease; Caucasians; Cause of Death; Cessation of life; Chest; Clinical; Clinical Data; Cohort Studies; Complex; Coronary; Country; Data; Data Collection; Development; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; European; Event; Foundations; Gene Expression; Genes; Genetic screening method; Genotype; Health Services Accessibility; Human; In Vitro; Income; Individual; K-Series Research Career Programs; Laboratories; Leadership; Measurement; Measures; Medial; Medical History; Mentorship; Methods; Molecular; Molecular Biology; Molecular Epidemiology; Molecular Genetics; N-Cadherin; Obesity; Pathway interactions; Physiologic pulse; Play; Population Group; Population Study; Predisposition; Prevention; Proteins; RNA; Race; Reading; Recruitment Activity; Research; Resources; Risk; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Staging; Testing; Thick; Time; Training; Translating; Ultrasonography; Variant; Vascular calcification; Woman; X-Ray Computed Tomography; aged; angiogenesis; base; beta catenin; calcification; cardiovascular disorder epidemiology; cardiovascular disorder risk; career; disease phenotype; frizzled related protein-3; high risk; human WISP1 protein; image archival system; improved; indexing; insight; intimal medial thickening; mRNA Expression; men; mortality; novel; peripheral blood; personalized care; protein expression; public health relevance; racial difference; racial/ethnic difference; receptor; research study; skills

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death worldwide and more than 80% of these deaths occur in low- and middle-income countries. The global burden of CVD has accelerated the need to better understand its epidemiology, identification, and treatment, particularly in high-risk and understudied population groups. African ancestry individuals have a higher risk of CVD events and mortality compared to European ancestry individuals and this racial/ethnic difference is not explained by traditional CVD risk factors or access to healthcare alone. Although mechanisms for the race differences in CVD epidemiology are complex and multifactorial, it is clear that molecular and genetic differences in susceptibility play an important role. Emerging evidence, primarily from animal models and in vitro experiments, indicates that the Wingless (Wnt) signaling pathway plays a role in angiogenesis, vascular calcification, and atherosclerosis. However, less is known about the role of the Wnt signaling pathway in CVD in humans. In addition, human studies have focused on only a limited subset of Wnt related proteins and have not assessed other key components of the Wnt signaling pathway in CVD. Our preliminary data in African ancestry men and women with a functional and race specific missense variant (Ala64Thr) in the Wnt co-receptor, Frizzled-1 (FZD1), revealed greater carotid ultrasound intima-media thickness compared to those with the wild-type genotype (Ala64Ala). In order to more comprehensively quantify the association between the Wnt pathway and subclinical CVD in humans, we will utilize data from our large, ongoing cohort study of African ancestry men aged =40 years. We are currently performing abdominal and chest CT scans for a study of ectopic adiposity and diabetes in 1200 African ancestry men. During this study, we are also obtaining and archiving images of carotid artery ultrasound and brachial-ankle pulse-wave velocity. These data will form the basis of the Aims of this proposal, which are to quantify the association between blood levels of Wnt pathway gene and protein expression with measures of subclinical CVD including coronary and aortic artery calcification, common carotid intima-media thickness and adventitial diameter, brachial-ankle pulse-wave velocity and ankle-brachial index in 365 men of African ancestry. We will also perform genotype-directed recruitment of 100 men with a known functional variant in the FZD1 gene and test for a difference in measures of subclinical CVD between variant carriers and non-carrier controls that will be recruited from the general study population. The successful completion of these research aims, along with an intensive training and mentorship plan, will provide the applicant with new skills and "hands-on" training in five major areas: epidemiologic field research, deeper subclinical CVD phenotyping, and training in cardiovascular physiology, molecular epidemiology laboratory training and grantsmanship. This Career Development Award will provide the applicant with protected time for didactic training and development of new skills that will lay the foundation for an independent research career in the molecular epidemiology of subclinical CVD.

 描述（由申请人提供）：心血管疾病 (CVD) 是全球死亡的主要原因，其中 80% 以上的死亡发生在低收入和中等收入国家。CVD 的全球负担加速了更好地了解其疾病的需要。流行病学、识别和治疗，特别是在高风险和未充分研究的人群中，与欧洲血统个体相比，非洲血统个体的 CVD 事件和死亡风险更高，并且这种种族/民族差异并不存在。尽管CVD流行病学中的种族差异的机制是复杂且多因素的，但很明显，易感性的分子和遗传差异发挥着重要作用，主要来自动物模型和研究。体外实验表明 Wnt 信号通路在血管生成、血管钙化和动脉粥样硬化中发挥作用，但人们对 Wnt 信号通路在人类 CVD 中的作用知之甚少。此外，人类研究仅关注 Wnt 相关蛋白的有限子集，并没有评估 CVD 中 Wnt 信号通路的其他关键成分。我们对具有功能和种族特异性错义变异 (Ala64Thr) 的非洲血统男性和女性的初步数据。与野生型基因型 (Ala64Ala) 相比，Wnt 共受体 Frizzled-1 (FZD1) 显示颈动脉超声内膜中层厚度更大。为了全面量化 Wnt 通路与人类亚临床 CVD 之间的关联，我们将利用我们对年龄 = 40 岁的非洲血统男性进行的大型队列研究的数据，我们目前正在进行腹部和胸部 CT 扫描，以研究异位肥胖和疾病。在这项研究中，我们还获取并存档了颈动脉超声和臂踝脉搏波速度的图像，这些数据将构成以下研究的基础。该提案的目的是通过亚临床心血管疾病的测量，包括主动脉钙化、颈总动脉内膜中层厚度和外膜直径、臂踝脉搏波，量化冠状动脉血液中 Wnt 通路基因和蛋白表达之间的关系我们还将对 365 名非洲血统男性进行基因型定向招募，其中 100 名男性具有已知的 FZD1 基因功能变异。并测试将从一般研究人群中招募的变异携带者和非携带者对照之间亚临床CVD测量的差异。成功完成这些研究目标以及强化培训和指导计划将为申请人提供帮助。该职业发展奖将提供五个主要领域的新技能和“实践”培训：流行病学现场研究、更深入的亚临床CVD表型分析、心血管生理学培训、分子流行病学实验室培训和资助。申请人有受保护的时间进行教学培训和开发新技能，这将为亚临床CVD分子流行病学的独立研究生涯奠定基础。