BAF60c and abdominal aortic aneurysm

BAF60c 和腹主动脉瘤

基本信息

批准号：
10297104
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/10297104
关键词：
Abdomen Abdominal Aortic Aneurysm Address Affect Age Aneurysm Angiotensin II Aorta Apoptosis Atherosclerosis Attention Attenuated Automobile Driving Blood Vessels Cardiovascular system Catalytic Domain Cathepsins Cells Cellular biology ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Co-Immunoprecipitations Complement Complex Contractile Proteins DNA Data Development Diabetes Mellitus Elastases 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 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 SMARCA4 gene 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 base brahma chromatin remodeling differential expression 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.

项目摘要/摘要腹部主动脉瘤（AAA）是由于越来越高的患病率而成为主要的医学问题破裂后的死亡率。尽管血管炎症，细胞外基质（ECM）降解，并且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主要的药物疗法以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。这将由对驱动发作的分子和细胞机制的更深入，更全面的理解， AAA的进展和结果。染色质重塑改变基因表达已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中的作用在很大程度上仍然存在未知。 BAF60家族包括三个相互排斥的开关/蔗糖非 - 可发酵（SWI/SNF）染色质重塑复合物。与心血管领域相关，他们玩控制脂质稳态，能量代谢（BAF60A），粒细胞（BAF60B）和心脏的重要作用（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的发展中的潜在作用。我们最近报道，VSMC中BAF60A的损失可通过减少血管炎症来防止实验AAA 小鼠的ECM降解。值得注意的是，BAF60C是VSMC中表达的最丰富的BAF60亚基。我们的初步数据表明，BAF60C在两者的腹主动脉瘤组织中都被下调人类和老鼠。 VSMC BAF60C敲除极大地加剧了弹性酶引起的AAA，并敲除人主动脉平滑肌细胞中的BAF60C降低了SMC收缩蛋白的表达并增加炎症基因和MMP9表达。我们假设VSMC特异性的BAF60C减弱了AAA 通过保持VSMC收缩表型并抑制血管炎症和ECM来开发降解。在体外，与AAA相关的刺激中，使用功能丧失和功能丧失，我们独特的VSMC- 特定的BAF60C敲除和转基因小鼠，两种已建立的鼠AAA模型在体内和一个集成工作流程，我们将（AIM 1）证明VSMC特异性的BAF60C会减弱AAA的形成，并注意通过scrnaseq改变了细胞轮廓和细胞间串扰，并为治疗提供了概念验证靶向和（AIM 2）使用VSMC稳态中BAF60C的保护机制在体外使用相关的刺激和RNASEQ，CHIP-SEQ和共免疫沉淀。这项工作将提供独特的机械关于各种和不同风险因素如何转化为VSMC功能障碍的见解，导致AAA并提供开发AAA新型疗法的基础。