Role of intercellular communication in the regulation of cardiac function

心脏的主要功能是向血液传递能量，以产生并维持为器官提供足够血流所需的动脉血压。人的心脏由多种类型的细胞组成，然而，心肌细胞(CMS)和心脏成纤维细胞(CFs)构成了心脏的重要组成部分，在心脏生理功能中起着至关重要的作用。心肌细胞是终末分化的细胞，心脏功能的急剧变化取决于结构的适应。近年来，心肌细胞间旁分泌活动被证明是心脏生理学的重要调节因子。血管功能主要由血管内皮细胞(ECs)、血管平滑肌细胞(VSMCs)和外膜组织调节。人体内的大部分血管都被脂肪组织包围着。这些细胞/组织之间的相互作用在很大程度上涉及到血管功能。近年来，血管周围脂肪细胞通过其对ECs和SMC的旁分泌活动来调节血管功能。*细胞间的通讯对于多细胞生物体的发育和环境适应是必不可少的。细胞之间通过细胞外分子进行交流。真核细胞释放被称为细胞外小泡(EVS)的复杂结构，可以以更复杂的方式影响遇到这些结构的细胞。EVS被广泛地细分为不同的类别：微粒子、微囊、外切体等。外切体是直径30-100 nm的活跃分泌的内吞纳米囊。胞外体携带着包括mRNAs、microRNAs、蛋白质和脂类在内的一系列分子，因此在遗传信息交换中起着关键作用。新的证据表明，受体细胞对外切体摄取的反应具有表达和功能上的变化。最近，心脏和血管细胞分泌的外切体被证明具有强大的细胞功能调节作用。*总体假设：胞外体细胞间通讯在心血管生理的调节中起着关键作用*我们的研究计划将概述特定的目标和研究问题，旨在解决以下具体目标：*1.表征CF源外体的货物，并确定它们在调节心肌细胞功能和心脏生理学中的作用。*2.表征血管周围脂肪细胞衍生的外体的货物，并研究它们在调节血管功能中的作用。*3.评估外体货物的性别差异及其影响。我们的研究将鉴定来自不同类型心血管细胞的胞外体，并可能为细胞间通讯在心血管生理学中的作用提供重要的新信息。

The primary function of a heart is to impart energy to blood to generate and sustain an arterial blood pressure necessary to provide adequate perfusion of organs. A human heart is composed of various cell types; however, the cardiomyocytes (CMs) and cardiac fibroblasts (CFs) constitute a significant mass of the heart and play a critical role in cardiac physiological function. The cardiomyocytes are terminally differentiated cells, and acute changes in cardiac function depend on the structural adaptations. Recently, the paracrine activity between cardiac cells has been shown to be a critical regulator of cardiac physiology. ******Vascular function is regulated primarily by endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and adventitial tissue. Most of the vessels in the human body are surrounded by the adipose tissue. The interactions among these cells/tissues are substantially involved in the vascular function. Recently, the perivascular adipocytes have shown to regulate vascular function by their paracrine activity on the ECs and SMCs. ******Cell-to-cell communication is essential for the development and environmental adaptation of multicellular organisms. Cells communicate with each other via extracellular molecules. Eukaryotic cells release complex structures called extracellular vesicles (EVs) which can affect cells that encounter these structures in a much complicated way. The EVs are broadly subdivided into different categories: microparticles, microvesicles, exosomes, etc. Exosomes are actively secreted endocytic nanovesicles with 30-100 nm diameter. Exosomes carry a composite cargo of molecules, including mRNAs, microRNAs, proteins, and lipids, and therefore plays a pivotal role in the exchange of genetic information. Emerging evidence suggests that recipient cells respond to exosome uptake with expressional and functional changes. Recently exosomes secreted from cardiac and vascular cells have shown to possess potent cell-function modulatory effects. ******Overarching Hypothesis: Exosomal intercellular communication plays a critical role in the regulation of cardiovascular physiology******Our research proposal will outline specific aims and research questions that are designed to address the following specific objectives:***1. To characterize the cargo of CF-derived exosomes and identify their role in the regulation of cardiomyocyte function and cardiac physiology.***2. To characterize the cargo of perivascular adipocyte-derived exosomes and study their role in the regulation of vascular function.***3. To evaluate the sex-based differences in exosomal cargo and their effects on cardiovascular physiology.******Our study will identify the exosomal cargo from various cardiovascular cell types and may provide a critical novel information about the role of intercellular communications in the cardiovascular physiology.