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BAF60c and abdominal aortic aneurysm

BAF60c 和腹主动脉瘤

基本信息

批准号：
10650179
负责人：
Jifeng Zhang
金额：
$ 54.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650179
关键词：
Abdominal Aortic Aneurysm Address Affect Age Aneurysm Angiotensin II Aorta Apoptosis Atherosclerosis Attention Attenuated Automobile Driving Blood Vessels Cardiovascular system Catalytic Domain Cathepsins Cell Separation Cells Cellular biology ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Co-Immunoprecipitations Complement Complex Contractile Proteins DNA Data Development Diabetes Mellitus Elastases Elderly Eligibility Determination Energy Metabolism Environment Epigenetic Process Extracellular Matrix Degradation Family Family member Functional disorder Gene Expression Genes Heart Homeostasis Human Hyperlipidemia Hypertension In Vitro Incidence Individual Inflammation Inflammatory Knock-in Mouse Knock-out Knockout Mice Ligands Link Lipids LoxP-flanked allele MMP9 gene Maps Medial Mediating Medical Metabolic Molecular Mus Operative Surgical Procedures Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phenotype Play Prevalence Primary Prevention Process Promoter Regions Receptor Signaling Regulation Reporting Risk Factors Role Rupture Sampling Scheme Sex Differences Smoking Smooth Muscle Myocytes Stains Stimulus Sucrose Therapeutic Thoracic Aortic Aneurysm Tissue Sample Tissues Transducers Transgenic Mice Translating Vascular Smooth Muscle Viral Vector Work abdominal aorta brahma chromatin remodeling differential expression gain of function genetic association genomic locus granulocyte high risk in vivo in vivo Model insight knock-down loss of function male member mortality mortality risk mouse model novel novel therapeutics p65 prevent promoter protein expression recruit repaired response sex therapeutic target transcription factor transcriptome sequencing vascular inflammation

项目摘要

PROJECT SUMMARY/ABSTRACT Abdominal Aortic Aneurysm (AAA) is a primary medical concern due to the increasing prevalence and high mortality rate upon rupture. Although vascular inflammation, extracellular matrix (ECM) degradation, and subsequent vascular smooth muscle cells (VSMCs) apoptosis are pathologic features and drivers of AAA, efforts to manipulate these processes did not yet result in any effective drug therapies beyond primary prevention, creating an urgent need for new drug-based therapeutic strategies. This will be facilitated by a deeper and comprehensive understanding of the molecular and cellular mechanisms driving onset, progression, and outcomes of AAA. Chromatin remodeling altering gene expression has been linked to most pathophysiologic conditions, including atherosclerosis and diabetes, but its role in AAA remains largely unknown. The BAF60 family comprises three mutually exclusive subunits of the SWItch/Sucrose Non- Fermentable (SWI/SNF) chromatin remodeling complex. Of relevance to the cardiovascular field, they play essential roles in controlling lipid homeostasis, energy metabolism (BAF60a), granulocyte (BAF60b) and heart (BAF60c) development. We found that BAF60a, b and c are differentially expressed in human and mouse AAA tissues, suggesting a potential role of the BAF60 subunits in VSMC biology and the development of AAA. We recently reported that loss of BAF60a in VSMCs prevents experimental AAA by reducing vascular inflammation and ECM degradation in mice. Remarkably, BAF60c is the most abundant BAF60 subunit expressed in VSMC. Our preliminary data show that BAF60c is downregulated in the abdominal aortic aneurysmal tissue in both humans and mice. VSMC BAF60c knockout significantly aggravates elastase-induced AAA, and knockdown of BAF60c in human aortic smooth muscle cells reduced the SMC contractile protein expression and increased inflammatory genes and MMP9 expression. We hypothesize that VSMC-specific BAF60c attenuates AAA development by maintaining the VSMC contractile phenotype, and inhibiting vascular inflammation and ECM degradation. Using gain- and loss-of-function in HASMCs in vitro, AAA-relevant stimuli, our unique VSMC- specific BAF60c knockout and transgenic mice, two established murine AAA models in vivo, and an integrated workflow, we will (Aim 1) Demonstrate that VSMC-specific BAF60c attenuates AAA formation with attention to altered cellular profiles and intercellular cross-talk by scRNAseq and provide proof-of-concept for therapeutic targeting and (Aim 2) Determine the protective mechanisms of BAF60c in VSMC homeostasis in vitro using relevant stimuli and RNAseq, ChIP-seq and co-immunoprecipitation. This work will provide unique mechanistic insights on how various and varying risk factors translate into VSMC dysfunction leading to AAA and provide the basis for developing novel therapies for AAA.

项目概要/摘要腹主动脉瘤 (AAA) 是一个主要的医学问题，因为其患病率不断增加且发病率高破裂时的死亡率。尽管血管炎症、细胞外基质（ECM）降解和随后的血管平滑肌细胞 (VSMC) 凋亡是 AAA 的病理特征和驱动因素，操纵这些过程的努力尚未导致除了初级疗法之外的任何有效的药物疗法预防，迫切需要新的基于药物的治疗策略。这将通过一个对驱动发病的分子和细胞机制有更深入和全面的了解， AAA 的进展和结果。染色质重塑改变基因表达与大多数病理生理状况，包括动脉粥样硬化和糖尿病，但其在 AAA 中的作用仍然很大程度上未知。 BAF60家族包括三个互斥的开关/蔗糖非-亚基可发酵 (SWI/SNF) 染色质重塑复合物。与心血管领域相关，他们发挥在控制脂质稳态、能量代谢 (BAF60a)、粒细胞 (BAF60b) 和心脏方面发挥重要作用（BAF60c）开发。我们发现 BAF60a、b 和 c 在人和小鼠 AAA 中差异表达组织，表明 BAF60 亚基在 VSMC 生物学和 AAA 发展中的潜在作用。我们最近报道，VSMC 中 BAF60a 的缺失可通过减少血管炎症来预防实验性 AAA 和小鼠 ECM 降解。值得注意的是，BAF60c 是 VSMC 中表达最丰富的 BAF60 亚基。我们的初步数据表明，BAF60c 在腹主动脉瘤组织中下调人类和老鼠。 VSMC BAF60c 敲除显着加重弹性蛋白酶诱导的 AAA，并且敲除人主动脉平滑肌细胞中的 BAF60c 降低 SMC 收缩蛋白表达并增加炎症基因和 MMP9 表达。我们假设 VSMC 特异性 BAF60c 减弱 AAA 通过维持 VSMC 收缩表型、抑制血管炎症和 ECM 来促进发育降解。利用体外 HASMC 的功能获得和丧失、AAA 相关刺激，我们独特的 VSMC- 特定的 BAF60c 敲除和转基因小鼠，两个已建立的体内小鼠 AAA 模型，以及一个集成的工作流程中，我们将（目标 1）证明 VSMC 特异性 BAF60c 会减弱 AAA 形成，并注意通过 scRNAseq 改变细胞特征和细胞间串扰，并为治疗提供概念验证靶向和（目标 2）确定 BAF60c 在体外 VSMC 稳态中的保护机制相关刺激和 RNAseq、ChIP-seq 和免疫共沉淀。这项工作将提供独特的机制关于各种不同的风险因素如何转化为导致 AAA 的 VSMC 功能障碍的见解，并提供开发 AAA 新疗法的基础。