Gender Differences in Experimental Aortic Aneurysms

实验性主动脉瘤的性别差异

• 批准号: 7477775
• 负责人: Gilbert Rivers Upchurch
• 金额: $ 44.98万
• 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/7477775
• 关键词: Abdomen; 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 A; 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岁高加索男性的第十大死因，2000年死亡总数接近16,000人。了解腹主动脉瘤的病理生理学是一项重要的工作。临床上，多种危险因素与AAA的发展有关，包括年龄增加、阳性吸烟史和高血压。男性性别也是患AAA的公认风险因素，男女比例为4：1。造成这种性别差异的原因尚不清楚。AAAs的形成机制是复杂的、多因素的。组织学上，AAA的特征是早期趋化因子驱动的白细胞渗入主动脉壁，随后由于局部过度产生基质降解酶而破坏中膜和外膜中的弹性蛋白和胶原，以及随着主动脉壁变薄而导致的平滑肌细胞丢失。目前，尚无治疗主动脉瘤患者的药物，仅以粗略的主动脉直径测量作为临界值，患者必须接受危及生命且昂贵的开放或血管内手术。因此，明确AAA形成的性别差异的早期机制是至关重要的，也将是本次研究的重点。了解基于性别的疾病模式的差异可能使我们能够开发新的翻译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差异是由荷尔蒙(雄激素：雌激素比率)调节白细胞进入主动脉壁所调节的。明确AAA形成过程中男性早期炎性细胞募集加速的机制。研究将检验这一假设，即男性AAA发病率的增加是由于雄激素相对于雌激素的过量导致白细胞增加到主动脉壁的次要原因。具体目的2.证明性腺激素可用于调节伴随AAA形成的炎症反应。研究将验证改变雄激素的假设：雌激素环境可以通过改变上述特定的可溶性介质依赖的白细胞运输来决定动脉瘤形成的流行程度，最终推动基质降解和修复朝着动脉瘤形成的平衡。