GATA4 as a Modulator of Aortic Root Sensitivity to Mechanochemical Disruptions Caused by an Aneurysm-causing Mutation

GATA4 作为主动脉根部对动脉瘤突变引起的机械化学破坏敏感性的调节剂

• 批准号: 10462239
• 负责人: Emily Eloise Bramel
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2025-08-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462239
• 关键词: Affect; Alleles; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Segment; Appearance; Applications Grants; Architecture; Arteries; Biology; Blood Vessels; Cardiovascular system; Cells; Communication; Complex; Cytoskeleton; Data; Defect; Development; Disease; Dissection; Echocardiography; Educational process of instructing; Elastic Fiber; Extracellular Matrix; Focal Adhesions; GATA4 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Global Change; Heterogeneity; Histologic; Impairment; In Situ; In Vitro; Inherited; Integrins; Intrinsic factor; Laboratories; Learning; Length; Location; Loeys-Dietz Syndrome; Maps; Mechanical Stress; Mediator of activation protein; Mentors; Molecular; Multiprotein Complexes; Mus; Mutate; Mutation; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphorylation; Plant Roots; Positioning Attribute; Postdoctoral Fellow; Predisposition; Process; RNA; Research; Research Personnel; Risk; Role; Rupture; Science; Scientist; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Structural defect; Structure; Technology; Testing; Thoracic Aortic Aneurysm; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transmission Electron Microscopy; Trees; Universities; Validation; Vascular Smooth Muscle; ascending aorta; career; computerized tools; disorder risk; experience; improved; in vivo; mortality; mouse model; postnatal; recruit; response; single-cell RNA sequencing; skills; symposium; therapy development; transcription factor; transcriptomics; undergraduate student

PROJECT SUMMARY Aortic aneurysms are localized dilations that predispose the vessel to dissection or rupture, both of which are associated with high mortality. Loeys-Dietz Syndrome (LDS) is a hereditary aneurysm disorder caused by mutations that impair, but do not fully disrupt, TGF-β signaling. LDS patients have a strong predisposition for disease in the aortic root even though the genes that are mutated in this condition are ubiquitously expressed throughout the vasculature. The mechanisms that underlie this localized vulnerability remain unclear. In this proposal, I will test the hypothesis that intrinsic factors expressed in smooth muscle cells present in the aortic root render them more susceptible to the mechanochemical disruptions of the aorta caused by LDS mutations. Specifically, I will investigate if intrinsic expression of Gata4 in a subset of vascular smooth muscle cells primes these cells to upregulate GATA4 when homeostatic inhibitory mechanisms that depend on proper contacts between these cells and the extracellular matrix fail. I will be supported by my sponsor, Dr. MacFarlane, and co-sponsor, Dr. Dietz, to complete the following aims. In Aim 1, I will uncover how LDS mutations affect aortic extracellular matrix structure and signaling downstream of focal adhesions and examine the effect of pharmacological interference with these pathways on aneurysm pathogenesis. In Aim 2, I will clarify the role of GATA4 in the pathogenesis of aortic root aneurysm by examining the effect of postnatal smooth muscle specific deletion of Gata4 on aortic root dilation. With the help of my collaborator, Dr. Kagohara, who is an expert in spatial transcriptomics, I will also learn use this cutting-edge technology and related computational tools to map the gradient of transcriptional heterogeneity along the length of the aorta. I will further develop my skills as an independent researcher and enhance my expertise in cardiovascular biology by completing focused coursework and regularly attending and presenting at scientific conferences. To improve my skills in scientific communication, I will seek out additional mentoring and teaching opportunities, including teaching an undergraduate genetics course at Johns Hopkins University. By completing this proposal, I will acquire the experience and skills necessary to attain a position as a postdoctoral fellow, and ultimately establish an independent academic career in cardiovascular research.

项目概要 主动脉瘤是局部扩张，使血管容易发生夹层或破裂，这两种情况都是 Loeys-Dietz 综合征 (LDS) 是一种遗传性动脉瘤疾病，与高死亡率相关。 损害但不完全破坏 TGF-β 信号传导的突变患者具有强烈的易感性。 主动脉根部疾病，尽管在这种情况下突变的基因普遍表达 这种局部脆弱性的机制尚不清楚。 建议，我将检验以下假设：平滑肌细胞中表达的内在因子存在于 主动脉根部使它们更容易受到主动脉机械化学破坏的影响 具体来说，我将研究 Gata4 在血管平滑肌亚群中的内在表达。 当稳态抑制机制依赖于肌肉细胞时，肌肉细胞会促使这些细胞上调 GATA4 这些细胞和细胞外基质之间的适当接触失败了，我将得到我的赞助商 Dr. 的支持。 MacFarlane 和共同发起人 Dietz 博士，为了完成以下目标 在目标 1 中，我将揭示 LDS 如何实现。 突变影响主动脉细胞外基质结构和粘着斑下游信号传导并检查 在目标 2 中，我将探讨药物干扰这些途径对动脉瘤发病机制的影响。 通过考察产后效应阐明GATA4在主动脉根部动脉瘤发病机制中的作用 在我的合作者 Dr. 的帮助下，平滑肌特异性删除 Gata4 对主动脉根扩张的影响。 鹿儿原先生是空间转录组学方面的专家，我也将学习使用这项尖端技术并 相关的计算工具来绘制沿主动脉长度的转录异质性梯度。 将进一步发展我作为独立研究员的技能并增强我在心血管方面的专业知识 通过完成重点课程并定期参加科学会议并在会上发表演讲来学习生物学。 提高我的科学交流技能，我将寻求更多的指导和教学机会， 包括在约翰·霍普金斯大学教授本科遗传学课程。 提案，我将获得获得博士后职位的经验和必要的技能，并且 最终在心血管研究领域建立了独立的学术生涯。