Rab27a functions in the vascular microenvironment

Rab27a 在血管微环境中发挥作用

• 批准号: 10490964
• 负责人: Caitlin Patricia Stieber
• 金额: $ 3.22万
• 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/10490964
• 关键词: 3-Dimensional; Address; Adipocytes; Adipose tissue; Affect; Atherosclerosis; Blood; Blood Vessels; Blood capillaries; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; 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; 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; 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; macrophage; 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.

心血管疾病是美国死亡的主要原因。心血管疾病的发生率 随着肥胖症的流行而增加。血管周围脂肪组织（PVAT）围绕大多数血管 身体并调节潜在的血管，在肥胖和之间提供局部细胞联系 心血管功能。在代谢健康的个体中，PVAT诱导抗增生性和 平滑肌细胞的血管瘤表型。相反，在肥胖个体中，PVAT引起 血管收缩。因为PVAT的旁分泌信号传导调节血管生理，所以我们预测 PVAT中的脂肪细胞是对血管疾病易感性的重要决定因素。我们的实验室有 以前表明，在饮食诱导的模型中，小鼠PVAT中的运输分子Rab27a增加了 肥胖症，也在人类PVAT中表达，这些PVAT来自心血管疾病的患者。更远， 在人类PVAT衍生的前脂肪细胞中抑制Rab27a功能会抑制其分化。这 项目将研究RAB27A控制人类PVAT衍生祖细胞中脂肪形成的机制。 此外，该项目将决定人脂肪细胞中Rab27a表达的变化如何改变他们 向血管平滑肌细胞发出信号。我们假设Rab27a控制着促进的分泌 脂肪因子脂肪因子，这些脂肪因子既调节前脂肪细胞，又可能是血管 平滑肌细胞。为了测试这些想法，我们已经建立了一个正在进行的人类的收藏和银行 来自不同水平心血管疾病的供体的PVAT。一组由正在接受的患者组成 由于严重的冠状动脉疾病，冠状动脉搭桥术（CABG），第二组包括 接受二尖瓣修复的患者没有血管疾病。对于每个样本，我们得出主要 来自基质血管分数的前脂肪细胞培养物。每个主要的主要前脂肪细胞种群 已经建立了捐助者类型。我们还开发了独特的三维人脂形圈模型 更紧密地模仿体内PVAT的组织。有了这些独特的人类细胞模型，我们的 提案将针对两个目标。 AIM 1将确定RAB27A调节脂肪形成的机制 人类PVAT衍生的脂肪细胞祖细胞。 AIM 2将确定在PVAT衍生的脂肪细胞中的RAB27A 影响旁分泌分泌和平滑肌细胞。这些研究将提供有关有关的新信息 Rab27a在血管微环境中的功能及其如何修饰脂肪因子的分泌和 潜在的血管活性因子。将来，我想成为一名板凳研究人员，这个研究项目是一个 出色的训练工具可以帮助我发展和提高自己的技能，例如使用人类的实验设计 比较组织，翻译研究的经验以及分子和细胞特征的分析 捐助者的临床特征。通过这项奖学金，我将有机会发展必要的技能 成为一名独立的研究科学家。