BLRD Research Career Scientist Award Renewal

项目摘要/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 将这些发现转化为确定新的分子靶点和预防和干预策略 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，这将为理解VSMC的发展提供新的见解 动脉粥样硬化、糖尿病血管病变和血管老化。利用新型组织特异性基因敲除小鼠 模型中，我们发现了成骨转录因子Runx2在调节VSMC中的重要作用 向骨样细胞重新编程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Runx2背后的新机制 氧化应激和高血糖导致血管系统表达上调；并发现了一种Runx2- VSMC、巨噬细胞和血管干细胞之间的依赖串扰在血管内皮生长发育中的作用 动脉粥样硬化钙化。通过这些创新的研究项目，我能够提供培训和 指导许多研究生、博士后研究员以及初级科学家和内科医生 伯明翰VAMC和阿拉巴马大学伯明翰分校(UAB)。我们努力调查这一事件 心血管疾病的潜在机制和确定的靶点汇集了越来越多的 伯明翰退伍军人医学中心和UAB的内科科学家和基础科学家的数量 为发展退伍军人管理局资助的计划项目奖和我的三个功绩审查奖，包括 激动人心且与VA高度相关的研究《糖尿病血管钙化的分子调控》(2019- 2023年)。此外，我们关于VSMC在动脉粥样硬化中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笔R01赠款的支持 健康。这些正在进行的研究不仅将阐明 血管疾病和衰老的发病机制，也为进一步研究提供了新的分子见解 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 跨度和生活质量，以及降低医疗成本。

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.