Mechanisms of sex-biased risk and resiliency in aneurysm and dissection

动脉瘤和夹层的性别偏见风险和弹性机制

• 批准号: 10705715
• 负责人: Sarah J Parker
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705715
• 关键词: Adhesions; Affect; Age; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Arterial Disorder; Automobile Driving; Biological; Biology; Blood Vessels; Candidate Disease Gene; Case Study; Cause of Death; Cell Lineage; Cell model; Cells; Collaborations; Complement; Core Facility; Coronary artery; Development; Diagnosis; Disease; Disease Management; Disease Progression; Disparate; Dissection; Estrogens; Event; Exhibits; Exposure to; FBN1; Female; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic Diseases; Germ Cells; Gonadal Steroid Hormones; Heart; Hormones; Human; Image; In Vitro; Infusion procedures; Inherited; Integrins; Knowledge; Marfan Syndrome; Mediating; Molecular; Molecular Profiling; Mus; Mutation; Myocardial Infarction; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Ploidies; Predisposition; Pregnancy; Prevalence; Prevention; Progesterone; Prognosis; Proteomics; Regulation; Risk; Risk Factors; Severities; Sex Bias; Sex Chromosomes; Sex Differences; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Study models; Techniques; Testing; Therapeutic; Treatment outcome; Trees; United States; Validation; Woman; Work; X Chromosome; acute coronary syndrome; arm; causal variant; cell type; disorder prevention; experimental study; female sex hormone; genome wide association study; hormonal signals; improved; in vitro Model; in vivo; induced pluripotent stem cell; innovation; insight; male; men; mouse model; new therapeutic target; novel strategies; phosphoproteomics; prevent; protective pathway; receptor expression; resilience; response; sex; single-cell RNA sequencing; social; stem cell model; steroid hormone; subcutaneous; therapeutic target; young woman

PROJECT SUMMARY / ABSTRACT Arterial dysfunction is a causal factor in the leading causes of death in the United States. Sex differences in the presentation, resiliency and risk profile of arterial pathologies are well established, yet knowledge to clarify the molecular determinants of these differences remain sparse. Aortic aneurysms and dissections exhibit clear and consistent sex differences in their presentation and treatment outcomes. Women are diagnosed significantly less frequently and at later ages than males, even in cases of hereditary aneurysm such as Marfan Syndrome (MFS) where causal mutations are inherited with equal frequency between males and females. When diagnosed, however, women exhibit poorer outcomes and prognosis relative to men for reasons likely attributable to both biological and socially driven factors. The biological underpinnings driving resiliency against aortic aneurysms and dissections in women remain unclear, but their definition will 1) identify protective pathways in females that could be leveraged to improve disease prevention and management in males and 2) understand the drivers of reduced resiliency in the females who do exhibit severe disease. In this proposal, we leverage a well-established mouse model of MFS, gonadectomy and hormone replacement, and cutting-edge proteomics in order to examine how the female sex hormones estrogen (E2) and progesterone (P4) intersect with chromosomally defined sex to affect well established AoR aneurysm phenotype (Aim 1). We will then combine in vitro experiments in human iPSC-models of normal and MFS vascular cells with in vivo validation in mice in order to test two specific hypotheses regarding how E2 and P4 affect known pathways involved in aneurysm pathogenesis; Angiotensin II (Ang II) signaling (Aim 2) and mechano/matrixsensing imbalance driven by specific integrin heterodimers (Aim 3). Interestingly, while severe of aortic root (AoR) aneurysm and dissection appear biased toward males, non- atherosclerotic Spontaneous Coronary Artery Dissection (SCAD) is clearly biased toward females and is a leading cause of acute coronary syndromes in young women. Among its risk factors are pregnancy and existing hereditary arteriopathies, such as Marfan Syndrome (MFS). Interestingly, Fibrillin-1 (Fbn1), the gene that causes MFS, has been identified as a candidate gene among patients with SCAD in recent genome wide association studies. Key molecular differences between the aortic and coronary arteries may confer critical molecular variance in response to hormones that results in disparate risk and resiliency due to sex. As an additional exploratory arm in each of the above Aims, we will investigate whether coronary artery pathology demonstrate ‘mirror image’ risk or resiliency signatures between hormone-altered male and female MFS mice in an effort to provide some of the first fundamental models for the study of the female-biased condition of SCAD. The insights gained from our studies will reveal putative risk and resiliency mechanisms that can be leveraged for prevention and therapeutic strategies applicable to both sexes.

项目概要/摘要 动脉功能障碍是美国性别差异的主要原因。 动脉病理的表现、弹性和风险状况已得到充分确立，但尚需了解澄清动脉病理的知识 这些差异的分子决定因素仍然稀疏。 其表现和治疗结果存在一致的性别差异，女性的诊断率明显较低。 即使是马凡氏综合症 (MFS) 等遗传性动脉瘤，其发病频率也比男性晚 男性和女性之间的因果突变遗传频率相同。 然而，相对于男性，女性表现出较差的结果和预后，原因可能归因于这两个因素 生物和社会驱动因素驱动主动脉瘤的恢复能力。 女性的解剖仍然不清楚，但他们的定义将 1）确定女性的保护途径 可以用来改善男性的疾病预防和管理，2）了解疾病的驱动因素 确实表现出严重疾病的女性的弹性降低 在这项提案中，我们利用了一个成熟的方法。 MFS、性腺切除和激素替代以及尖端蛋白质组学的小鼠模型，以检查 女性性激素雌激素 (E2) 和黄体酮 (P4) 如何与染色体定义的性别相交叉 影响已确定的 AoR 动脉瘤表型（目标 1），然后我们将结合人体体外实验。 正常和 MFS 血管细胞的 iPSC 模型，在小鼠体内进行验证，以测试两种特定的 关于 E2 和 P4 如何影响动脉瘤发病机制的已知途径的假设； II (Ang II) 信号传导 (目标 2) 和由特定整合素异二聚体驱动的机械/基质传感失衡 (目标 3）匿名，虽然严重的主动脉根部（AoR）动脉瘤和夹层似乎偏向男性，但非 动脉粥样硬化性自发性冠状动脉夹层术 (SCAD) 明显偏向于女性，并且是一种 年轻女性急性冠状动脉综合征的主要原因是怀孕和现有的疾病。 遗传性动脉病，例如马凡氏综合症（MFS）。 MFS，在最近的全基因组关联中被确定为 SCAD 患者的候选基因 主动脉和冠状动脉之间的关键分子差异可能赋予关键的分子特征。 对激素的反应存在差异，导致因性别而导致不同的风险和弹性。 在上述每个目标的探索性臂中，我们将研究冠状动脉病理学是否证明 激素改变的雄性和雌性 MFS 小鼠之间的“镜像”风险或弹性特征，旨在 为研究 SCAD 女性偏向状况提供了一些第一个基本模型。 从我们的研究中获得的结果将揭示可用于预防的假定风险和弹性机制 以及适用于两性的治疗策略。