BAF60c and abdominal aortic aneurysm

BAF60c 和腹主动脉瘤

• 批准号: 10474527
• 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
• 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/10474527
• 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; Elderly; 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

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.

项目总结/摘要 腹主动脉瘤（AAA）是一个主要的医疗问题，由于日益增加的患病率和高 破裂时的死亡率。虽然血管炎症，细胞外基质（ECM）降解， 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还没有产生任何有效的药物治疗， 预防，迫切需要新的基于药物的治疗策略。这将由一个 更深入和全面地了解推动发病的分子和细胞机制， AAA的进展和结果。染色质重塑改变基因表达与大多数 病理生理条件，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BAF 60家族包括SWITCH/Sucrose Non-3的三个相互排斥的亚基。 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（BAF 60 a）、粒细胞（BAF 60 b）和心脏中起重要作用 （BAF 60 c）开发。我们发现BAF 60 a、B和c在人和小鼠AAA中的表达存在差异 组织，表明BAF 60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BAF 60 a的缺失通过减少血管炎症来预防实验性AAA 和ECM降解。值得注意的是，BAF 60 c是VSMC中表达最丰富的BAF 60亚基。 我们的初步数据显示，BAF 60 c在两组的腹主动脉瘤组织中下调， 人类和老鼠VSMC BAF 60 c基因敲除可显著抑制弹性蛋白酶诱导的AAA， BAF 60 c在人主动脉平滑肌细胞中降低SMC收缩蛋白表达， 炎症基因和MMP 9表达。我们假设VSMC特异性BAF 60 c可减弱AAA， 通过维持VSMC收缩表型，抑制血管炎症和ECM， 降解使用体外HASMCs功能的获得和丧失，AAA相关刺激，我们独特的VSMC- 特异性BAF 60 c敲除和转基因小鼠，两种建立的小鼠AAA体内模型，以及整合的 工作流程，我们将（目的1）证明VSMC特异性BAF 60 c可减弱AAA形成，并注意 通过scRNAseq改变细胞特征和细胞间串扰，并为治疗性药物提供概念验证。 （目的2）利用体外培养的血管平滑肌细胞模型， 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械 了解各种不同的风险因素如何转化为导致AAA的VSMC功能障碍，并提供 开发AAA新疗法的基础。