CCDC92 and cardiovascular disease

CCDC92与心血管疾病

• 批准号: 10567132
• 负责人: Yanbo Fan
• 金额: $ 53.92万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567132
• 关键词: Accounting; American; Animal Model; Aorta; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biogenesis; Biological Process; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Separation; Cell physiology; Cessation of life; Clinical; Code; Coiled-Coil Domain; Coronary heart disease; Crossbreeding; Data; Development; Diabetes Mellitus; Disease; Epidemic; Event; Foundations; Functional disorder; Future; Genetic; Genetic Transcription; Genetic study; Glucose; Goals; High Fat Diet; Histologic; Human; Human Biology; Impairment; In Vitro; Inflammation; Insulin Resistance; Knock-in Mouse; Knock-out; Knockout Mice; Lysosomes; Measures; Mediating; Methods; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral Vascular Diseases; Phenotype; Prevalence; Prevention; Reporting; Research; Role; Smooth Muscle Myocytes; Stimulus; Stroke; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Variant; Vascular Smooth Muscle; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; clinically relevant; diabetic; diabetic patient; euglycemia; experimental study; genetically modified cells; human disease; in vivo; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; protective effect; statistics; transcription factor

ABSTRACT Among patients with diabetes, cardiovascular diseases (CVDs) are the primary cause of their mortality. Reducing CVD risk is a critical clinical goal for treating diabetic patients. Diabetes exacerbates atherosclerosis development and progression, which is the major cause of many CVD, including heart attacks, strokes, and peripheral vascular disease. Vascular smooth muscle cell (VSMC) dysfunction contributes to the pathogenesis of atherosclerosis throughout all the stages. The genetic relationship between diabetes and CVD provides the promise for the prevention and treatment of both disorders. Recent genetic studies have demonstrated that the specific variants at the coiled-coil domain containing 92 (CCDC92) locus are associated with both type 2 diabetes (T2D) and coronary heart disease (CHD). The biological function and detailed mechanisms by which CCDC92 regulates these diseases, a necessary step towards the ultimate goal of targeting CCDC92, remain unclear. Our preliminary data demonstrated that Ccdc92 knockout inhibits high-fat diet-induced insulin resistance and atherosclerosis in mice. We further present extensive preliminary studies showing that CCDC92 induces proatherogenic phenotypes, contributing to atherosclerosis pathogenesis. Here we hypothesize that VSMC CCDC92 promotes atherosclerosis development and progression by regulating the lysosomal pathway. By taking advantage of our unique animal models combined with molecular, cellular, histological approaches, we will define the role of CCDC92 in proatherogenic phenotypes in VSMCs in vitro (Aim 1); Determine the role of CCDC92 in atherosclerosis under diabetic and euglycemic conditions in vivo (Aim 2). Successful completion of the proposed study would provide a deep understanding of how CCDC92 elicits atherosclerosis and will likely set a profound foundation to define CCDC92 as a novel therapeutic target to treat atherosclerosis and diabetes-associated CVD.

抽象的 在糖尿病患者中，心血管疾病（CVD）是其死亡的主要原因。 降低 CVD 风险是治疗糖尿病患者的关键临床目标。糖尿病加剧动脉粥样硬化 发展和进展，这是许多心血管疾病的主要原因，包括心脏病发作、中风和 周围血管疾病。血管平滑肌细胞（VSMC）功能障碍导致发病机制 动脉粥样硬化的各个阶段。糖尿病和心血管疾病之间的遗传关系提供了 有望预防和治疗这两种疾病。最近的遗传学研究表明， 包含 92 (CCDC92) 位点的卷曲螺旋结构域的特定变异与 2 型 糖尿病（T2D）和冠心病（CHD）。其生物学功能和详细机制 CCDC92对这些疾病进行调节，是实现针对CCDC92的最终目标的必要步骤，仍然 不清楚。我们的初步数据表明，Ccdc92 敲除可抑制高脂饮食诱导的胰岛素 小鼠的抵抗力和动脉粥样硬化。我们进一步提出广泛的初步研究表明 CCDC92 诱导促动脉粥样硬化表型，促进动脉粥样硬化发病机制。这里我们假设 VSMC CCDC92 通过调节溶酶体途径促进动脉粥样硬化的发生和进展。 通过利用我们独特的动物模型与分子、细胞、组织学方法相结合， 我们将在体外定义 CCDC92 在 VSMC 致动脉粥样硬化表型中的作用（目标 1）；确定角色 体内糖尿病和血糖正常条件下 CCDC92 在动脉粥样硬化中的作用（目标 2）。顺利完成 拟议的研究将深入了解 CCDC92 如何引起动脉粥样硬化，并将 可能为将 CCDC92 定义为治疗动脉粥样硬化和动脉粥样硬化的新治疗靶点奠定了深厚的基础。 糖尿病相关的CVD。