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Pericyte reprogramming in fibrosis

纤维化中的周细胞重编程

基本信息

批准号：
10578526
负责人：
Anjelica Gonzalez
金额：
$ 48.73万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578526
关键词：
3-Dimensional Actins Acute Adopted Adoption Affect Animal Model Area Automobile Driving Biochemical Biocompatible Materials Biological Assay Biology Biomedical Engineering Blood Vessels Blood capillaries Cell Adhesion Molecules Cells Chemicals Chronic Clinical Deposition Development Diagnosis Disease Dropout Endothelium Epithelial Cells Event Exposure to Extracellular Matrix Extracellular Matrix Proteins Fibrosis Functional disorder Growth Growth Factor Health Heart Homeostasis Human In Situ Individual Inflammation Inflammatory Influentials Integrins Interstitial Lung Diseases Intervention Investigation Kidney Knowledge Lesion Liver Lung MCAM gene Maintenance Mechanics Mediating Mediator Metabolic Methods Microvascular Dysfunction Mitochondria Molecular Molecular Biology Monitor Myofibroblast Organ Pathologic Pathway interactions Patients Pericytes Permeability Phenotype Polymers Population Process Profibrotic signal Publishing Pulmonary Fibrosis RNA marker Regulation Role Sampling Severity of illness Signal Transduction Skin Smooth Muscle Source Staging System Structure Technology Therapeutic Therapeutic Intervention Time Tissues Transforming Growth Factor beta Transforming Growth Factors Translating Vascular remodeling Work cell type clinically relevant design disease diagnosis experience in vitro Model interstitial mechanical signal mouse model necrotic tissue prevent programs protein biomarkers response stem stem cell biomarkers stem cells stem-like cell therapeutically effective transcriptome sequencing vascular contributions vascular injury

项目摘要

Prior to clinical evidence of fibrosis, microvascular injury occurs, presenting as an altered functional state of the endothelium, increased permeability, enhanced vasoreactivity, increased expression of adhesion molecules, excessive inflammation, and altered vascular wall growth. Microvascular rarefaction, or capillary dropout, is coincident with chronic fibrosis, and considered an accelerator of the disease. However little is known about the microvascular contribution to fibrotic diseases in which microvasculature are key to tissue health and homeostasis. Given the central role of the vasculature in barrier function, inflammatory regulation and interstitial tissue necrosis, it is likely that the microvasculature, specifically, mural perivascular cells (pericytes), are key contributors to fibrotic development and progression. Recent evidence suggests that microvascular dysfunction may be more directly influential to tissue remodeling than epithelial cells. Limited availability of human pericytes from a readily available human source has led to an incomplete understanding of the mechanisms underlying pericyte to myofibroblast transition that facilitate both microvascular and interstitial matrix remodeling. Our work, supported by that of others in this area, has led us to the hypothesis that pericytes cease homeostatic maintenance of the microvasculature by transition into a myofibroblast through the process of dedifferentiation and re-differentiation known as cellular reprogramming. As myofibroblasts, cells of pericyte lineage contribute to interstitial tissue fibrosis. Through three distinct aims we will show that, in response to growth factor, pericytes deposit extracellular matrix proteins to alternatively support vascular stability and fibrosis as they undergo phenotypic transition from microvascular pericytes to interstitial myofibroblasts. We also determine points in pericyte transition that may be key for therapeutic intervention. We utilize traditional molecular biology methods and biomaterials technology to determine the profibrotic mediators promote functional and phenotypic shifts in pericytes. Using 2- and 3-D bioengineered mechanically and biochemically tunable polymer based extracellular matrices, we decouple the role of biochemical and mechanical signals in regulation of PC to myofibroblast transition through the process of reprogramming. Results acquired through use of human cells in bioengineered structures will be validated with animal models of pulmonary fibrosis.

在纤维化的临床证据之前，发生微血管损伤，表现为微血管的功能状态改变。内皮，增加的渗透性，增强的血管反应性，增加的粘附分子表达，过度炎症和改变的血管壁生长。微血管稀疏或毛细血管脱落，与慢性纤维化同时发生，并被认为是疾病的加速剂。然而，人们对它知之甚少。微血管对纤维化疾病的贡献，其中微血管是组织健康的关键，体内平衡鉴于血管系统在屏障功能、炎症调节和间质中的核心作用组织坏死，很可能是微血管，特别是壁周细胞（周细胞），是关键纤维化发展和进展的贡献者。最近的证据表明微血管功能障碍可能比上皮细胞更直接地影响组织重塑。人周细胞的可用性有限从一个现成的人力资源，导致了不完整的理解的机制，周细胞向肌成纤维细胞的转变促进微血管和间质基质重塑。我们的工作，在这一领域的其他人的支持下，使我们假设周细胞停止稳态通过以下过程转变为肌成纤维细胞来维持微血管系统：去分化和再分化称为细胞重编程。作为肌成纤维细胞，周细胞谱系有助于间质组织纤维化。通过三个不同的目标，我们将表明，在周细胞响应生长因子，存款细胞外基质蛋白，以支持血管稳定性和纤维化，因为它们经历从微血管周细胞到间质肌成纤维细胞的表型转变。我们还可以确定周细胞转变的点，这可能是治疗干预的关键。我们利用传统分子生物学方法和生物材料技术，以确定促纤维化介质促进周细胞的功能和表型转变。使用2-D和3-D生物工程机械和生化可调聚合物为基础的细胞外基质，我们解耦的作用，生化和机械信号，通过重编程过程调节PC向肌成纤维细胞的转变。通过使用获得的结果将用肺纤维化的动物模型来验证生物工程结构中的人类细胞。