Rab27a functions in the vascular microenvironment

心血管疾病是美国人死亡的主要原因。心血管疾病的发病率 随着肥胖症的流行而沿着增加。血管周围脂肪组织（PVAT）围绕着大多数血管， 调节身体和底层血管，提供肥胖和肥胖之间的局部细胞联系， 心血管功能在代谢健康的个体中，PVAT诱导抗增殖和 平滑肌细胞的血管舒张表型。相反，在肥胖个体中，PVAT诱导 血管收缩由于PVAT的旁分泌信号调节血管生理学，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。本实验室 先前表明，在饮食诱导的小鼠PVAT模型中，运输分子RAB 27 a增加， 肥胖的人PVAT中表达，并且还在源自心血管疾病患者的人PVAT中表达。此外，本发明还 在人PVAT衍生的前脂肪细胞中抑制RAB 27 a功能会抑制它们的分化。这 该项目将研究RAB 27 a控制人PVAT衍生祖细胞脂肪形成的机制。 此外，该项目将确定人脂肪细胞中RAB 27 a表达的变化如何改变其生物学特性。 向血管平滑肌细胞发出信号。我们推测，RAB 27 a控制着前- 这些脂肪因子调节前脂肪细胞和潜在的血管 平滑肌细胞为了验证这些想法，我们建立了一个持续收集和储存人类 来自不同心血管疾病水平供体的PVAT。一组是接受 冠状动脉旁路移植术（CABG）由于严重的冠状动脉疾病，第二组包括 接受二尖瓣修复术的患者，无血管疾病。对于每一个样本，我们得到主要的 前脂肪细胞培养物来自基质血管部分。几个原代前脂肪细胞群体， 捐助者类型已确定。我们还开发了一个独特的三维人体脂肪球模型 以更接近地模拟体内PVAT的组织。有了这些独特的人类细胞模型， 这项建议有两个目的。目的1将确定RAB 27 a调节脂肪形成的机制。 人PVAT衍生的脂肪细胞祖细胞。目的2将确定RAB 27 a在PVAT衍生的脂肪细胞中如何表达。 影响旁分泌和平滑肌细胞。这些研究将提供新的信息， RAB 27 a在血管微环境中的功能及其如何调节脂肪因子的分泌， 潜在的血管活性因子。在未来，我想成为一个板凳研究员，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，如实验设计使用人类 组织，转化研究的经验，以及比较的分子和细胞特征分析 捐赠者的临床特征。通过这个奖学金，我将有机会发展必要的技能 成为一名独立的研究科学家

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.