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.

项目摘要 主动脉瘤是局部扩散，使血管易于解剖或破裂，这两者都是 与高死亡率有关。 Loeys-Dietz综合征（LDS）是由遗传性动脉瘤疾病。 损害但不会完全破坏TGF-β信号的突变。 LDS患者对 即使在这种情况下突变的基因无处不在，疾病即使在这种情况下突变的基因 通过脉管系统。该本地化漏洞的基础的机制尚不清楚。在这个 提案，我将检验以下假设： 主动脉根使它们更容易受到由主动脉的机械化学破坏。 LDS突变。具体而言，我将研究gata4的固有表达在血管平滑的子集中 当依赖于稳态的抑制性机制时 这些细胞和细胞外基质之间的适当接触失败。我的赞助商博士将为我提供支持。 MacFarlane和共同发起人Dietz博士完成了以下目标。在AIM 1中，我会发现LDS如何 突变影响主动脉外基质结构和局灶性粘合剂下游的信号传导，并检查 药物干扰这些途径对动脉瘤发病机理的影响。在AIM 2中，我会 通过检查产后的作用，阐明GATA4在主动脉根动脉瘤的发病机理中 GATA4在主动脉根部扩张上的平滑肌特异性缺失。在我的合作者博士的帮助下 空间转录组学专家Kagohara，我还将学习使用这种尖端技术和 相关的计算工具绘制沿主动脉长度的转录异质性梯度的梯度。我 将进一步发展我作为独立研究人员的技能，并增强我在心血管方面的专业知识 通过完成专注的课程工作，定期参加和在科学会议上展示生物学。到 提高我在科学沟通方面的技能，我将寻找其他心理和教学机会， 包括在约翰·霍普金斯大学（Johns Hopkins University）教授本科遗传学课程。通过完成此操作 提案，我将获得获得博士后研究员职位所必需的经验和技能，并且 最终在心血管研究领域建立了独立的学术生涯。