Rab27a functions in the vascular microenvironment

Rab27a 在血管微环境中发挥作用

• 批准号: 10597700
• 负责人: Caitlin Patricia Stieber
• 金额: $ 3.37万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597700
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Affect; Aorta; Atherosclerosis; Blood Vessels; Blood capillaries; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; Cell Differentiation process; Cell model; Cell physiology; Cells; Characteristics; Clinical; Coculture Techniques; Collagen Fiber; Collection; Coronary Arteriosclerosis; Coronary Artery Bypass; Data; Development; Diagnosis; Disease; Disease Progression; Endothelial Cells; Environment; Epidemic; Experimental Designs; Fatty acid glycerol esters; Fellowship; Future; Hand; Heart Abnormalities; Human; In Vitro; Individual; Laboratories; Link; Lipids; Macrophage; Mediating; Metabolic; Methods; Mitral Valve; Modeling; Molecular; Molecular Analysis; Mus; Nerve; Obesity; Operative Surgical Procedures; Paracrine Communication; Pathogenicity; Pathology; Patients; Persons; Phenotype; Physiology; Population; Predisposition; Prevalence; Production; Proliferating; Proteins; Publications; Research; Research Personnel; Research Project Grants; Role; Sampling; Scientist; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; T-Lymphocyte; Testing; Tissue Donors; Tissue Expansion; Tissue Sample; Training; Translational Research; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Work; adipocyte differentiation; adipokines; atherogenesis; cardiac repair; congenital heart disorder; cytokine; diet-induced obesity; experience; experimental study; human tissue; improved; in vivo; interest; knock-down; lipid biosynthesis; mortality; mouse model; novel; obese person; paracrine; progenitor; repaired; skills; stem cells; trafficking; translational study; vasoconstriction

Cardiovascular disease is the leading cause of death in the USA. Rates of cardiovascular disease have increased along with the prevalence of obesity. Perivascular adipose tissue (PVAT) surrounds most vessels in the body and regulates the underlying blood vessel, providing a local cellular link between obesity and cardiovascular function. In metabolically healthy individuals, PVAT induces an antiproliferative and vasorelaxation phenotype of smooth muscle cells. Conversely, in obese individuals, PVAT induces vasoconstriction. Because paracrine signaling from PVAT regulates vascular physiology, we predict that the adipocytes within PVAT are an important determinant of susceptibility to vascular disease. Our laboratory has previously shown that the trafficking molecule RAB27a is increased in mouse PVAT in a model of diet induced obesity, and also is expressed in human PVAT derived from patients with cardiovascular disease. Further, suppression of RAB27a function in human PVAT-derived preadipocytes inhibits their differentiation. This project will study the mechanism by which RAB27a controls adipogenesis in human PVAT-derived progenitors. Further, this project will determine how changes in RAB27a expression in human adipocytes changes their signaling to vascular smooth muscle cells. We hypothesize that RAB27a controls the secretion of pro- adipogenic adipokines and that these adipokines regulate both preadipocytes and potentially also vascular smooth muscle cells. To test these ideas, we have established an ongoing collection and banking of human PVAT from donors with different levels of cardiovascular disease. One group consists of patients undergoing coronary artery bypass grafting (CABG) due to severe coronary artery disease, and a second group includes patients undergoing mitral valve repair, without vascular disease. For each sample, we derive primary preadipocyte cultures from the stromal vascular fraction. Several primary preadipocyte populations from each donor type have been established. We also developed a unique three-dimensional human adiposphere model to more closely mimic the organization of PVAT in vivo. With these unique human cell models in hand, our proposal will address two aims. Aim 1 will identify the mechanism by which RAB27a regulates adipogenesis in human PVAT-derived adipocyte progenitor cells. Aim 2 will identify how RAB27a in PVAT-derived adipocytes affects paracrine secretion and smooth muscle cells. These studies will provide novel information about RAB27a function in the vascular microenvironment and how it modifies the secretion of adipokines and potential vasoactive factors. In the future, I want to be a bench researcher, and this research project is an excellent training vehicle to help me develop and improve my skills such as experimental design using human tissues, experience in translational research, and analysis of molecular and cellular characteristics compared to clinical features of donors. Through this fellowship, I will have the opportunity to develop the necessary skills to be an independent research scientist.

在美国，心血管疾病是主要的死亡原因。心血管疾病的发病率 随着肥胖症的流行而增加。血管周围脂肪组织(PVAT)包围着大多数血管。 并调节潜在的血管，在肥胖和肥胖之间提供一种局部细胞联系 心血管功能。在代谢健康的个体中，PVAT诱导抗增殖和 平滑肌细胞的血管松弛表型。相反，在肥胖者中，PVAT诱导 血管收缩。因为来自PVAT的旁分泌信号调节血管生理，我们预测 PVAT内的脂肪细胞是血管疾病易感性的重要决定因素。我们的实验室有 先前显示，在饮食诱导的小鼠PVAT模型中，运输分子RAB27a增加 肥胖，也在来自心血管疾病患者的人类PVAT中表达。此外， 抑制人PVAT来源的前脂肪细胞RAB27a功能可抑制其分化。这 该项目将研究RAB27a控制人类PVAT来源的祖细胞脂肪生成的机制。 此外，该项目将确定RAB27a在人类脂肪细胞中表达的变化如何改变其 向血管平滑肌细胞发出信号。我们假设RAB27a控制着PRO-2的分泌。 成脂脂肪因子以及这些脂肪因子调节前脂肪细胞和潜在的血管 平滑的肌肉细胞。为了测试这些想法，我们建立了一个持续的人类集合和数据库 来自患有不同程度心血管疾病的捐赠者的PVAT。其中一组患者接受了 由于严重的冠状动脉疾病而进行的冠状动脉搭桥术(CABG)，第二组包括 接受二尖瓣修补术的患者，无血管疾病。对于每个样本，我们推导出主要的 从基质血管部分培养前脂肪细胞。每个来源都有几个初级前脂肪细胞群体 供体类型已建立。我们还开发了一种独特的三维人体脂肪层模型。 以更接近地模拟PVAT在体内的组织。有了这些独特的人体细胞模型，我们的 该提案将解决两个目标。目标1将确定RAB27a调节脂肪形成的机制。 人PVAT来源的脂肪细胞前体细胞。AIM 2将确定RAB27a在PVAT来源的脂肪细胞中如何 影响旁分泌和平滑肌细胞。这些研究将提供有关 RAB27a在血管微环境中的作用及其如何调节脂肪因子和 潜在的血管活性因子。在未来，我想成为一名板凳研究员，而这个研究项目是一个 优秀的培训工具，帮助我发展和提高我的技能，如使用人类进行实验设计 组织，翻译研究的经验，分子和细胞特征的比较分析 捐献者的临床特征。通过这一奖学金，我将有机会发展必要的技能。 成为一名独立的研究科学家。