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; 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（由适用提供）：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的全球燃烧加速了更好地了解其流行病学，识别和治疗的需求，尤其是在高风险和知识的人口群体中。与欧洲血统相比，非洲血统的人患CVD事件和死亡率的风险更高，而传统的CVD危险因素或仅获得医疗保健的机会并不能解释这种种族/种族差异。尽管CVD流行病学中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起着重要作用。来自动物模型和体外实验的主要证据，表明无翼（WNT）信号通路在血管生成，血管计算和动脉粥样硬化中起作用。然而，关于Wnt信号通路在人类中CVD中的作用知之甚少。此外，人类研究仅集中在有限的WNT相关蛋白质的子集上，并且没有评估CVD中Wnt信号通路的其他关键组成部分。我们在WNT共受体毛躁1（FZD1）中具有功能和种族特异性错义变体（ALA64THR）的非洲血统男人和女性的初步数据显示，与具有野生型基因型（ALA644Ala）相比，我们的颈动脉超声型超声层厚度更大。为了更全面地量化人类中的Wnt途径和亚临床CVD之间的关联，我们将利用我们对非洲血统男子的大型，正在进行的队列研究中的数据= 40岁。我们目前正在进行腹部和胸部CT扫描，以研究1200名非洲血统男性的生态肥胖和糖尿病。在这项研究中，我们还获得了颈动脉超声和臂轴脉冲波速度的图像。这些数据将构成该提案的目的的基础，该数据将量化Wnt途径基因的血液水平与蛋白质表达之间的关联与亚临床CVD的测量，包括冠状动脉和主动脉动脉计算，常见的颈动脉内膜 - 内膜密度厚度和先进的直径，高级臂杆脉动脉波静脉高速级别和型号，均为365个男性n. 365。我们还将对FZD1基因中具有已知功能变异的100名男性进行基因型定向募集，并测试将从一般研究人群中募集的变体载体和非携带者对照组之间亚临床CVD的测量差异。这些研究的成功完成，以及密集的培训和心态计划，将在五个主要领域为申请人提供新的技能和“动手”培训：流行病学现场研究，更深层的亚临床CVD表型以及心血管生理学的培训，分子流行病学实验室培训和Grantmanship。该职业发展奖将为申请人提供受保护的时间进行教学培训和新技能的发展，这将为亚临床CVD分子流行病学的独立研究职业奠定基础。