Gender Differences in Experimental Aortic Aneurysms

实验性主动脉瘤的性别差异

• 批准号: 7632241
• 负责人: Gilbert Rivers Upchurch
• 金额: $ 46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632241
• 关键词: Abdominal Aortic Aneurysm; Accounting; Age; Age-Years; Androgen Antagonists; Androgen Receptor; Androgens; Aneurysm; Aorta; Aortic Aneurysm; Aromatase Inhibition; Automobile Driving; Bicalutamide; Bone Marrow Transplantation; CCL2 gene; CXCL2 gene; Caliber; Castration; Caucasians; Caucasoid Race; Cause of Death; Cells; Cessation of life; Chimera organism; Collagen; Complex; Development; Disease; Donor person; Elastin; Environment; Enzymes; Equilibrium; Estradiol; Estrogens; Extracellular Matrix Proteins; Female; Functional disorder; Gelatinase B; Gender; Gender Role; Genetic; Gonadal Hormones; Histologic; Hormonal; Hormone Receptor; Hormones; Human; Hypertension; IL8 gene; Incidence; Infiltration; Inflammatory; Inflammatory Response; Investigation; Knockout Mice; Letrozole; Leukocyte Trafficking; Leukocytes; Life; MMP2 gene; Measurement; Mediating; Mediator of activation protein; Medical; Modeling; Mus; Operative Surgical Procedures; Organ Transplantation; Pathogenesis; Patients; Pattern; Prevalence; Prevention approach; Production; Regulation; Relative (related person); Risk Factors; Role; Sampling; Secondary to; Selective Estrogen Receptor Modulators; Sex Characteristics; Smoking History; Smooth Muscle Myocytes; Supplementation; Tamoxifen; Testing; Testosterone; Tissues; Transplantation; Tunica Adventitia; Woman; base; chemokine; macrophage; male; men; neutrophil; receptor; repaired; research study; translational approach

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) comprise the 10th leading cause of death in Caucasian males 65-74 years of age and accounted for nearly 16,000 deaths overall in the year 2000. Understanding the pathophysiology of AAAs is an important undertaking. Clinically, multiple risk factors are associated with the development of AAAs, including increasing age, positive smoking history, and hypertension. Male gender is also a well-established risk factor for the development of an AAA with a 4:1 male to female ratio. The reason for this gender disparity is unknown. The pathogenesis of AAAs formation is complex and multifactorial. Histologically, AAAs are characterized by early chemokine driven leukocyte infiltration into the aortic wall with subsequent destruction of elastin and collagen in the media and adventitia by excessive local production of matrix degrading enzymes, and smooth muscle cell loss with thinning of the aortic wall. At present, there are no medical therapies available to treat patients with aortic aneurysms, using only the crude measurement of aortic diameter as a threshold for which patients must undergo life-threatening and costly surgery, either open or endovascularly. Therefore, defining the early mechanisms underlying gender-related differences in AAA formation are critical and will be the focus of the present investigation. Understanding differences in disease patterns based on gender may allow us to develop new translational approaches to the prevention and treatment of patients with aortic aneurysms. Overall hypothesis: Gender- related differences in aortic aneurysm formation are mediated by the hormonal (androgen: estrogen ratio) regulation of leukocyte trafficking into the aortic wall. Specific Aim 1. To define the mechanism by which early inflammatory cell recruitment is accelerated in males during AAA formation. Studies will test the hypothesis that increased incidence of AAAs in males is secondary to increased recruitment of leukocytes into the aortic wall driven by an excess of androgens relative to estrogens. Specific Aim 2. To demonstrate that gonadal hormones can be used to modulate the inflammatory response accompanying AAA formation. Studies will test the hypothesis that altering the androgen: estrogen environment can dictate the prevalence of aneurysm formation by altering the aforementioned specific soluble mediator dependent leukocyte trafficking, ultimately driving the balance of matrix degradation and repair toward aneurysm formation.

描述（由申请人提供）：腹主动脉瘤 (AAA) 是 65-74 岁白人男性的第十大死因，2000 年总共导致近 16,000 例死亡。了解 AAA 的病理生理学是一项重要的任务。临床上，多种危险因素与 AAA 的发生有关，包括年龄增长、吸烟史和高血压。男性也是 AAA 发展的一个公认的危险因素，男女比例为 4:1。这种性别差异的原因尚不清楚。 AAAs形成的发病机制是复杂的、多因素的。在组织学上，AAA 的特征是早期趋化因子驱动的白细胞浸润到主动脉壁，随后由于基质降解酶的局部过量产生而破坏中膜和外膜中的弹性蛋白和胶原蛋白，以及随着主动脉壁变薄而导致平滑肌细胞损失。目前，尚无可用于治疗主动脉瘤患者的药物疗法，仅使用主动脉直径的粗略测量作为阈值，患者必须接受危及生命且昂贵的手术，无论是开放手术还是血管内手术。因此，明确 AAA 形成中性别相关差异的早期机制至关重要，并将成为本研究的重点。了解基于性别的疾病模式差异可能使我们能够开发新的转化方法来预防和治疗主动脉瘤患者。总体假设：主动脉瘤形成的性别相关差异是由白细胞流入主动脉壁的激素（雄激素：雌激素比例）调节介导的。具体目标 1. 明确 AAA 形成过程中男性早期炎症细胞募集加速的机制。研究将验证以下假设：男性 AAA 发病率增加是由于雄激素相对于雌激素过量导致白细胞募集到主动脉壁增加所致。具体目标 2. 证明性腺激素可用于调节伴随 AAA 形成的炎症反应。研究将检验以下假设：改变雄激素：雌激素环境可以通过改变上述特定可溶性介质依赖性白细胞运输来决定动脉瘤形成的发生率，最终推动基质降解和修复的平衡，从而促进动脉瘤形成。