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: 10532033
• 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/10532033
• 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; Cells; Complement; Core Facility; Coronary artery; Development; Diagnosis; Disease; Disease Management; Disease Progression; Dissection; Estrogens; Event; Exhibits; Exposure to; FBN1; Female; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic Diseases; Gonadal Steroid Hormones; Heart; Hormones; Human; Image; In Vitro; Infusion procedures; Inherited; Integrins; Knowledge; Libido; Marfan Syndrome; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Myocardial Infarction; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Plant Roots; 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; receptor expression; resilience; response; sex; single-cell RNA sequencing; social; 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.

项目摘要 /摘要 动脉功能障碍是美国主要死亡原因的因果因素。性别差异 人工制品的陈述，弹性和风险概况已经建立，但知识以澄清 这些差异的分子决定素仍然很少。主动脉动脉瘤和解剖暴露于明确的和 其表现和治疗结果中的性别差异一致。妇女被诊断出明显较少 即使在遗传性动脉瘤（例如Marfan综合征（MFS））的情况下，通常都比男性了 在男性和女性之间以相等频率遗传的因果突变。诊断时， 但是，由于可能归因于男性的原因，妇女的结果和预后较差 生物和社会驱动因素。生物学基础推动对主动脉动脉瘤的弹性 妇女的解剖仍然不清楚，但其定义将为1）确定女性的受保护途径 可以利用以改善男性的预防疾病和管理，2）了解 确实表现出严重疾病的女性的弹性降低。在此提案中，我们利用了一个公认的 MFS的小鼠模型，促性腺切除术和替代马体和尖端的蛋白质组学 女性性激素雌激素（E2）和孕酮（P4）如何与染色体定义的性别相交 影响良好的AOR动脉瘤表型（AIM 1）。然后，我们将在人类中结合体外实验 在小鼠中具有体内验证的正常和MFS血管细胞的IPSC模型，以测试两个特定 关于E2和P4如何影响涉及动脉瘤发病机理的已知途径的假设；血管紧张素 II（ANG II）信号传导（AIM 2）和由特定整联蛋白异二聚体驱动的机械/基质传感不平衡（AIM 3）。有趣的是，虽然严重的主动脉根（主动脉）动脉瘤和剖析外观偏向男性，但非 - 动脉粥样硬化自发的冠状动脉剖析（SCAD）显然对女性有偏见，是一个 年轻女性急性冠状动脉综合征的主要原因。其危险因素包括怀孕和现有 遗传性动脉病，例如Marfan综合征（MFS）。有趣的是，纤维蛋白-1（FBN1），引起的基因 MFS在最近的基因组范围内的SCAD患者中已被确定为候选基因 研究。主动脉和冠状动脉之间的关键分子差异可能会导致关键分子 响应激素的差异导致性别导致不同的风险和弹性。另外 上述每个目标中的探索臂，我们将研究冠状动脉病理学是否证明 “镜像图像”风险或改变骑马的雄性和女性MFS小鼠之间的弹性特征 为研究女性偏见的SCAD疾病提供了一些第一个基本模型。见解 从我们的研究中获得的将揭示可以利用预防的假定风险和弹性机制 以及适用于男女的治疗策略。