Biomimetic Vascular Matrix for Vascular Smooth Muscle Cell Mechanobiology and Pathology

用于血管平滑肌细胞力学生物学和病理学的仿生血管基质

基本信息

批准号：
10586599
负责人：
Yongho Bae
金额：
$ 58.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2023-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586599
关键词：
3-Dimensional Abnormal Cell Affect Amino Acids Animal Model Aorta Arterial Injury Arteries Atherosclerosis Atomic Force Microscopy Attenuated Biochemical Biocompatible Materials Biological Biological Models Biology Biomechanics Biomimetics Biophysical Process Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Separation Cell physiology Cells Cellular biology Chromatin Coronary Arteriosclerosis Coronary heart disease Coupled DNA Sequence Alteration Data Development Disease Disease Progression Environment Event Extracellular Matrix Extracellular Matrix Proteins Family suidae Feedback Fluorescent in Situ Hybridization Gene Expression Genetic Transcription Goals Histologic Histology Human Hyperplasia Image In Vitro Injury Invaded Machine Learning Mechanics Mediating Medicine Microscopy Modeling Molecular Monitor Morphology Mus Nuclear Structure Optics Pathologic Pathologic Processes Pathology Pharmacotherapy Phenotype Physical condensation Physiological Production Proliferating Property Protein Family Proteins RNA Research Research Personnel Research Proposals Resolution Role Smooth Muscle Myocytes Structure System Testing Therapeutic Time Tissue Engineering Tissues Vascular Smooth Muscle Work arterial remodeling arterial stiffness cardiovascular risk factor cell behavior cell motility epigenomics femoral artery in vivo in vivo Model inhibitor-of-apoptosis protein injured knock-down machine learning algorithm member migration mouse model nanofiber nanoscale neointima formation new therapeutic target novel overexpression polyacrylamide hydrogels protein expression reconstruction response scaffold single cell analysis soft tissue survivin three dimensional cell culture transcriptome sequencing transcriptomics vascular abnormality vascular injury vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

SUMMARY Arterial stiffness is a key risk factor for cardiovascular disease (CVD) events. A change in arterial stiffness is a significant pathology in vascular injury, atherosclerosis, and coronary disease. Stiffening of the vessel wall promotes anomalous migration and proliferation of vascular smooth muscle cells (VSMCs), leading to neointima formation on the vessel wall. It is not clear, however, how the extracellular matrix (ECM) influences these pathological processes. This research proposal will address this by exploring how changes in arterial stiffness elicit VSMC behaviors that contribute to cardiovascular disease. Specifically, this work draws upon preliminary data revealing that the protein survivin is a key regulator of stiffness-mediated VSMC proliferation and migration and an effector of arterial stiffening and remodeling. Using mouse and human VSMCs, we will first explore how vascular ECM stiffness impacts VSMC migration, proliferation, and chromatin organization at the single-cell level (early stage of disease progression; Aim 1) and, second, determine how pathological ECM stiffness drives neointima formation, altering the local mechanical environment of VSMCs in vitro (advanced stage of disease progression; Aim 2). Lastly, we will confirm survivin’s role in regulating both ECM production and arterial stiffness (in vivo animal model; Aim 2). These aims will be achieved using 3D cell culture with a novel in vitro porcine decellularized aorta ECM-based fibrous scaffold system and mouse injury models. Briefly, VSMCs isolated from mouse and human aortas will be cultured on nanofibrous scaffolds of different stiffnesses and structures that mimic normal and pathological conditions in the body. The VSMC responses to pathological ECM stiffness will be analyzed using advanced microscopy to observe changes in cellular/nuclear structure and biomechanical properties in vitro, and the RNA and protein expression will be assessed at the single-cell level. Finally, arterial stiffness and VSMC function will be studied in intact arteries of injured mice; histology and biochemical analyses of dissected tissues will be conducted after arterial stiffness has been manipulated by arterial injury, drug treatment, or genetic mutations. This project will, for the first time, study the molecular and biophysical mechanisms by which survivin (i) mediates stiffness-sensitive VSMC functions and (ii) contributes to neointima formation and stiffening, revealing a completely new aspect of survivin biology in VSMCs and in the pathology of arterial stiffness. Overall, this proposal is unique in its ability to identify potential new therapeutic targets for the treatment of CVDs.

概括动脉僵硬度是心血管疾病 (CVD) 事件的一个关键危险因素。僵硬是血管损伤、动脉粥样硬化和冠状动脉疾病的重要病理学。血管壁的改变促进血管平滑肌细胞的异常迁移和增殖（VSMC），导致血管壁上新内膜形成，然而，尚不清楚是如何发生的。细胞外基质（ECM）影响这些病理过程。通过探索动脉僵硬度的变化如何引发有助于心血管的 VSMC 行为具体来说，这项工作利用的初步数据表明，生存蛋白是关键。僵硬度介导的 VSMC 增殖和迁移的调节因子以及动脉硬化的效应因子使用小鼠和人类 VSMC，我们将首先探讨血管 ECM 硬度如何变化。在单细胞水平（早期阶段）影响 VSMC 迁移、增殖和染色质组织疾病进展；目标 1)，其次，确定病理性 ECM 僵硬如何驱动新内膜形成，改变体外 VSMC 的局部机械环境（疾病晚期目标 2) 最后，我们将确认存活蛋白在调节 ECM 产生和动脉中的作用。硬度（体内动物模型；目标 2）将通过使用 3D 细胞培养和新颖的方法来实现。体外猪脱细胞主动脉 ECM 纤维支架系统和小鼠损伤模型。从小鼠和人类主动脉分离的 VSMC 将在不同的纳米纤维支架上培养模拟体内正常和病理状况的硬度和结构。将使用先进的显微镜来分析对病理性 ECM 僵硬的反应，以观察体外细胞/核结构和生物力学特性的变化，以及 RNA 和蛋白质最后，将在单细胞水平评估动脉僵硬度和 VSMC 功能。将在受伤小鼠的完整动脉中研究解剖组织的组织学和生化分析；在通过动脉损伤、药物治疗或遗传控制动脉僵硬度后进行该项目将首次研究突变的分子和生物物理机制。生存素 (i) 介导硬度敏感的 VSMC 功能，(ii) 有助于新内膜形成和变硬，揭示了 VSMC 中存活蛋白生物学和病理学的全新方面总体而言，该提案的独特之处在于它能够确定潜在的新治疗靶点。用于治疗CVD。