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Intrinsic Stiffness of Aortic Vascular Smooth Muscle Cell in the Development of Hypertension

高血压发展过程中主动脉血管平滑肌细胞的固有硬度

基本信息

批准号：
10275468
负责人：
Hongyu Qiu
金额：
$ 14.15万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10275468
关键词：
3-Dimensional Affect Aging Agonist Angiotensin II Aorta Area Attenuated Blood Pressure Blood Vessels Cardiovascular Diseases Cells Data Dependence Development Elderly Exhibits Foundations Funding Future Gene Proteins Genes Goals Hypertension In Vitro Inbred SHR Rats Inflammation Inflammation Mediators Inflammatory Interleukins Investigation Knockout Mice Knowledge Lead Ligands Light Link Measures Mediating Messenger RNA Microarray Analysis Modeling Molecular Mus Parents Pathogenesis Pathologic Processes Pathology Pathway interactions Play Principal Investigator Property Proteins Public Health Rattus Regulation Research Role Serum Response Factor Signal Pathway Signal Transduction Smooth Muscle Myocytes Testing Tissue Model Tissues Translating Up-Regulation Vascular Diseases Vascular Smooth Muscle Western Blotting Work base cardiovascular risk factor career development cytokine effective therapy extracellular hypertension treatment in vivo knock-down loss of function mechanical properties mouse model normotensive novel overexpression parent grant parent project prevent receptor receptor expression receptor function response transcription factor

项目摘要

PROJECT SUMMARY of the Supplement The parent project was proposed to investigate the role of the activation of SRF in aortic stiffening, however, the mechanisms underlying the increase of SRF in hypertensive VSMCs remains unknown. The work performed on the parent grant directly led to the identification of interleukin 36 receptor (IL-36R), an inflammatory regulator, which was dramatically increased in the hypertensive aortic tissue and VSMCs, and established a potential link of the IL-36R with SRF activation in hypertensive VSMCs. These new findings built the foundation of the present supplemental application. One of the goals of this supplement is to expand the research of the parent grant to explore the potential role of IL-36R in the development of aortic stiffening in hypertension and its association with SRF-mediated signaling. Another goal of this supplement is to support the candidate’s investigation in this new research area extended from the parent grant, and help her to become an R01-funded principal investigator in 1-2 years. Based on our preliminary data, we hypothesize that the upregulation of IL-36R contributes to aortic stiffness in hypertension by increasing VSMC stiffness through SRF-mediated signaling. We plan to test this hypothesis by pursuing the following specific aims: Aim 1: Determine the role of IL-36R in VSMC stiffness and its regulation on SRF–mediated signaling in vitro. We will use a gain- and loss-of-function strategy to identify IL-36R-dependent effects at the cell level. We will test whether overexpressing IL-36R in WKY VSMCs increases the VSMC stiffness, and whether knocking- down IL-36R results in a reversal of the enhanced stiffness of SHR VSMCs. In addition, we will use IL-36R agonists and antagonists to determine whether the effect of IL-36R requires activation by an IL-36 cytokine. The VSMCs stiffness will be measured by AFM and 3D constituted tissue models as we proposed in the parent grant. We will also determine whether overexpressing or knocking down IL-36R in VSMCs induces a parallel alteration on the SRF-mediated signaling by testing the key genes and proteins as demonstrated in the parent grant. Specific Aim 2: Determine the role of IL-36R in the development of aortic stiffening and hypertension in vivo. To accomplish this, we will determine whether IL-36R is necessary for the regulation of aortic stiffness by using a VSMC-specific IL-36R KO mouse model. We will test whether the deletion of IL-36R affects the aortic stiffening and blood pressure induced by Angiotensin II in these mice. The aortic stiffness will be measured both in vivo and ex vivo as we described in the parent proposal. The VSMC stiffness and involved signaling will be determined in the isolated TA VSMCs from these mice as proposed in the Aim1. We expect that this supplement will discover novel mechanisms that may link the IL-36R with SRF-mediated intracellular signaling which will lead to a better understanding in the pathogenesis of aortic stiffness in hypertension and to help the candidate ‘s career development.

增刊项目摘要