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The mechanistic role of surfactant protein A in smooth muscle cell phenotype modulation and vascular remodeling

表面活性蛋白A在平滑肌细胞表型调节和血管重塑中的机制作用

基本信息

批准号：
10516027
负责人：
Skylar Dawn King
金额：
$ 6.98万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2024-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10516027
关键词：
Angioplasty Animals Arterial Disorder Arteries Asthma Atherosclerosis Attenuated Blood Vessels Bypass Carotid Arteries Cell Differentiation process Cell Nucleus Cell Proliferation Contractile Proteins Data Development Diabetes Mellitus Diabetic Angiopathies Disease Environment Genes Genetic Transcription Goals Histologic Host Defense Hyperplasia In Vitro Inflammatory Response Injury Knock-out Knockout Mice Laboratories Lung MYH11 gene Malignant Neoplasms Mechanics Medial Mediating Mentors Missouri Modeling Molecular Mus Operative Surgical Procedures Pathogenesis Phenotype Phosphorylation Physiological Play Process Proteins Pulmonary Surfactant-Associated Protein A Rattus Recombinants Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stents Supplementation Surface Tension Systemic hypertension Testing Time Training Transforming Growth Factor beta Transplantation Universities Vascular Diseases Vascular Proliferation Vascular Smooth Muscle Vascular remodeling alpha Actin alveolar type II cell extracellular gain of function genetic approach human disease hydrophilicity in vivo loss of function mRNA Expression mouse model myocardin neointima formation neutralizing antibody novel promoter restenosis surfactant function targeted treatment therapy development vascular injury

项目摘要

PROJECT SUMMARY The overall goal of this proposal is to find novel mechanisms whereby surfactant protein A (SPA) regulates vascular smooth muscle cell (SMC) phenotype modulation. SMC transition from a differentiated to dedifferentiated phenotype in addition to neointima formation/vascular remodeling has a critical role in human diseases such as the development of atherosclerosis, restenosis after angioplasty or bypass, diabetic vascular complications, arteriopathy transplants, asthma and cancer. Mechanisms that regulate SMC phenotype modulation and neointima formation are not well understood. The physiological function of SPA is its secretion by type II alveolar cells to maintain minimal surface tension in the lungs. However, preliminary data indicate a role for SPA as a SMC phenotype modulator. In vivo, SPA was expressed in the medial and neointimal SMCs following mechanical injury in rat and mouse carotid arteries. The wire-injury induced intimal hyperplasia was dramatically attenuated in SPA knockout mice. Furthermore, increased mRNA expression of SMC contractile genes and key regulators for contractile SMC phenotype, Myocardin and TGF-β1 was observed in SMCs isolated from SPA knockout mice. Additionally, SMCs from SPA knockout mice had increased Smad3 phosphorylation and the increase was blocked by the TGF-β1 neutralizing antibody. SPA is localized in the nucleus of SMCs suggesting it may have a role in SMC gene transcription. Indeed, SPA deficiency increased smooth muscle α-actin and smooth muscle 22-α promoter activity whereas recombinant SPA protein attenuated their activities. Hence, the central hypothesis is that SPA regulates SMC phenotype modulation and vascular remodeling through both extracellular (via modulating TGF-β1 signaling) and intracellular (Myocardin-related gene transcription) mechanisms. Using primary culture of SMC, in vivo mouse wire injury models combined with molecular, cellular and histological approaches, this proposal will 1) determine the molecular extracellular and intracellular mechanisms by which SPA regulates SMC phenotypic modulation; and 2) determine if SPA is essential for SMC phenotype modulation/vascular remodeling in vivo. Project completion will uncover novel mechanisms regulating SMC phenotypic modulation and provide understanding into whether SPA is a potential target for therapy against vascular damage associated with common vascular diseases such as diabetes, restenosis, atherosclerosis and cancer. The training plan laid out by the sponsor and the outstanding environment in the mentor’s laboratory and at the University of Missouri will safeguard the successful completion of the proposed studies.

项目总结