BLRD Research Career Scientist Award Renewal

BLRD 研究职业科学家奖续展

• 批准号: 10346455
• 负责人: Yabing Chen
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346455
• 关键词: Aging; Alabama; Animal Model; Atherosclerosis; Award; Blood Vessels; Cardiovascular Diseases; Cell physiology; Cells; Circadian Dysregulation; Collaborations; Development; Diabetes Mellitus; Funding; Gene Expression Regulation; General Population; Goals; Grant; Health; Health Care Costs; Hyperglycemia; Intervention; Investigation; Longevity; Medical center; Mentors; Military Personnel; Mission; Molecular; Molecular Target; Oxidative Stress; Pathogenesis; Patient Care; Phenotype; Physicians; Postdoctoral Fellow; Prevention strategy; Quality of life; Regulation; Research; Research Personnel; Research Project Grants; Role; Scientist; Services; Smooth Muscle Myocytes; Therapeutic; Tissues; Training; Translating; United States National Institutes of Health; Universities; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; Veterans; bone; calcification; cardiovascular health; career; circadian pacemaker; diabetic; gene function; graduate student; improved; innovation; insight; knockout gene; macrophage; mouse model; new therapeutic target; next generation; novel; osteogenic; programs; stem cells; transcription factor

Project Summary/Abstract My major research focus is to understand the fundamental mechanisms of gene regulation and function in the development of cardiovascular disease, a major health burden for our veterans. Our overarching goals are to translate the findings into identification of novel molecular targets and strategies for prevention and intervention of cardiovascular disease. We have been studying the molecular regulation of vascular smooth muscle cells (VSMC) phenotypic transitions, which should provide new insights into the understanding of the development of atherosclerosis, diabetic vasculopathy and vascular aging. Using novel tissue-specific gene knockout mouse models, we have uncovered an essential role of the osteogenic transcription factor Runx2 in regulating VSMC reprogramming into bone-like cells, leading to the pathogenesis of vascular calcification and stiffness in animal models of atherosclerosis and diabetes. We have also uncovered novel mechanisms underlying Runx2 upregulation in the vasculature by increased oxidative stress and hyperglycemia; and discovered a Runx2- dependent crosstalk between VSMC, macrophages and vascular stem cells in the development of atherosclerotic calcification. With these innovative research programs, I have been able to provide training and mentoring to many graduate students, postdoctoral fellows and junior scientists and physicians at the Birmingham VAMC and affiliated University of Alabama at Birmingham (UAB). Our efforts to investigate the underlying mechanisms and identify targets for cardiovascular disease have brought together increasing numbers of physician scientists and basic scientists at the Birmingham VA medical center and UAB, which led to the development of a VA-funded Program Project Award and three of my Merit Review Awards, including the exciting and highly VA-related research “Molecular Regulation of Vascular Calcification in Diabetes” (2019- 2023). In addition, our collaborative research projects on the regulation of VSMC function in atherosclerosis, diabetes and vascular aging have also been supported by several R01 grants from the National Institutes of Health. These ongoing investigations will not only elucidate the molecular mechanisms underlying the pathogenesis of vascular disease and aging, but also provide novel molecular insights facilitating further studies to translate these findings into therapeutic strategies for patient care, so as to improve the veterans’ health, life span and quality of life, as well as reduce healthcare costs.

项目总结/摘要 我的主要研究重点是了解基因调控和功能的基本机制， 心血管疾病的发展，这是我们退伍军人的主要健康负担。我们的首要目标是 将这些发现转化为新的分子靶点的识别以及预防和干预策略 心血管疾病我们一直在研究血管平滑肌细胞的分子调控 （VSMC）表型转变，这应该提供新的见解的发展的理解， 动脉粥样硬化、糖尿病性血管病变和血管老化。利用新型组织特异性基因敲除小鼠 模型，我们已经发现了成骨转录因子Runx 2在调节VSMC中的重要作用 重编程为骨样细胞，导致动物血管钙化和僵硬的发病机制 动脉粥样硬化和糖尿病的模型。我们还发现了Runx 2的新机制 通过增加氧化应激和高血糖在血管系统中上调;并发现Runx 2- VSMC，巨噬细胞和血管干细胞之间的依赖性串扰， 动脉粥样硬化钙化通过这些创新的研究项目，我能够提供培训， 指导许多研究生，博士后研究员和初级科学家和医生在 伯明翰VAMC和伯明翰附属亚拉巴马大学（UAB）。我们努力调查 潜在的机制和确定心血管疾病的目标已经汇集了越来越多的 伯明翰VA医疗中心和UAB的许多医生科学家和基础科学家， 开发VA资助的计划项目奖和我的三个优秀评审奖，包括 令人兴奋和高度VA相关的研究“糖尿病血管钙化的分子调节”（2019- 2023年）。此外，我们在动脉粥样硬化中VSMC功能调节的合作研究项目， 糖尿病和血管老化也得到了美国国立卫生研究院的几项R 01赠款， 健康这些正在进行的研究不仅将阐明潜在的分子机制， 血管疾病和衰老的发病机制，而且还提供了新的分子见解，促进进一步的研究 将这些发现转化为患者护理的治疗策略，以改善退伍军人的健康，生活， 寿命和生活质量，以及降低医疗费用。