Gender Differences in Experimental Aortic Aneurysms

描述（由申请人提供）：腹主动脉瘤（AAAs）是65-74岁高加索男性死亡的第十大原因，在2000年总共造成近16,000人死亡。了解AAAs的病理生理学是一项重要的工作。临床上，多种危险因素与AAAs的发生有关，包括年龄增长、吸烟史和高血压。男性性别也是AAA（男女比例为4:1）发展的一个公认的风险因素。造成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。组织学上，AAAs的特征是早期趋化因子驱动的白细胞浸润到主动脉壁，随后介质和外膜中的弹性蛋白和胶原被过度的局部基质降解酶破坏，平滑肌细胞丢失，主动脉壁变薄。目前，还没有治疗主动脉瘤患者的医学疗法，只能使用粗略的主动脉直径测量作为阈值，患者必须接受危及生命和昂贵的手术，无论是开放手术还是血管内手术。因此，确定AAA形成中性别相关差异的早期机制至关重要，这将是本研究的重点。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转化方法来预防和治疗主动脉瘤患者。总体假设：性别相关的动脉瘤形成差异是由激素（雄激素：雌激素比）调节白细胞进入主动脉壁所介导的。具体目标确定男性在AAA形成过程中早期炎症细胞募集加速的机制。研究将验证一种假设，即男性AAAs发病率的增加是继发于相对于雌激素过量的雄激素导致白细胞向主动脉壁募集增加。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。研究将验证这样一个假设，即改变雄激素：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患病率，最终推动基质降解和修复的平衡，从而导致动脉瘤形成。

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.