Tissue Factor & Clot Formation In Abdominal Aortic Aneurysm

描述（由申请人提供）：候选人近期和长期目标的摘要。我的近期目标是在凝血和血栓形成领域的专家奈杰尔·麦克曼博士的指导下继续我的博士后培训。关于组织因子在血管疾病中的作用，我还有很多东西要向Mackman博士学习。我还想提高我的技能，作为一个研究科学家在学术领域和出版我的剩余项目从我目前的F32 NRSA补助金，如果获奖，K99研究在我的补助金建议。我的长期和最终职业目标是成为一名受人尊敬的学术科学家，其研究重点是了解心血管疾病的发生和进展，重点是腹主动脉瘤。像每一位科学家一样，我希望有一天能找到一种有效的治疗方法，减轻众多疾病患者的痛苦，延长生命质量和寿命。此外，我期待着教学和指导年轻科学家灌输的技术，知识和技能，已经教我和传播学术导师的持续循环。研究职业发展计划的关键要素摘要。在本培训计划期间，我将参加定期的实验室会议，与我的小组讨论相关数据和文献。另外，我会 我希望每年至少向该部门提交一次我的研究报告，以征求批评和反馈。为了增加我在心血管疾病的血管生物学和病理学领域的知识，我将旁听UNC-CH的几门课程。我还将参加校内和校外的几个研讨会，以加强我的写作和领导能力。UNC-CH每周和每月举办几次由该领域专家举办的研讨会，我将参加这些研讨会。我将继续前往科学会议，展示我的数据，并与科学界互动。最后，我将在K99阶段每周与我的导师会面，讨论我的结果和我研究的未来方向。项目摘要。腹主动脉瘤（AAA）影响5%-10%的65岁以上的男性和女性，是美国第13大死亡原因。AAA定义为动脉壁的永久性局部扩张，直径大于正常值的50%，是一种主动脉炎性疾病，可导致壁夹层、壁内凝块形成和主动脉破裂，在大多数情况下几乎立即导致死亡。重要的是，壁内凝块在AAA病因学中的作用仍然很少探索。 我们将检验壁内血凝块形成稳定AAA的一般假设。具体而言，我将研究组织因子（TF），凝血酶，血小板和蛋白酶激活受体（PARs）在AAAs的形成和发展中的作用。 我们将利用血管紧张素II（AngII）LDLr-/-小鼠AAA模型。我们将使用遗传学和药理学方法来调节不同蛋白质的表达和活性，并确定对AAA的影响。我的建议分为三个目标，第一个是指导，最后两个是独立的。目的1将确定TF在AngII诱导的AAA进展和破裂中的作用。我们假设TF凝血活性降低将减少促进AAA破裂的凝块形成，并且血管平滑肌细胞（VSMC）表达的TF和PAR-2降低将由于VSMC迁移减少而导致AAA扩张。目的2探讨凝血酶及其下游效应物纤维蛋白原和PAR-1在AAA中的作用。我们假设纤维蛋白原缺乏和抗凝治疗将减少凝块形成并导致AAA破裂增加，PAR-1缺乏将由于VSMC迁移减少而增加AAA。目的3探讨血小板及其凝血酶受体（PAR-4）在AAA中的作用。我们假设血小板PAR-4依赖性活化降低或抗血小板治疗将减少血栓形成并增加AAA破裂。总之，这些研究将增加我们对凝血级联反应、血小板和PAR在AAA发生、进展和破裂中的作用的理解。这项工作的临床意义在于， 抗血栓药物可能增加患者AAA破裂的风险。

DESCRIPTION (provided by applicant): Summary of Candidates Immediate and Long-term Goals. My immediate goals are to continue my postdoctoral training under the mentorship of Dr. Nigel Mackman, an expert in the field of coagulation and thrombosis. I still have much to learn from Dr. Mackman regarding the function of tissue factor in vascular disease. I would also like to advance my skills as a research scientist in the academic field and publish my remaining projects from my current F32 NRSA grant and, if awarded, the K99 studies proposed in my grant. My long-term and ultimate career goal is to become a respected academic scientist whose research is focused on understanding the initiation and progression of cardiovascular disease with a focus on abdominal aortic aneurysm. Like every other scientist, I hope to one day find an effective treatment to alleviate the suffering of multitudes of patients afflicted with diseases and prolong the quality and duration of life. In addition, I look forward to teaching and mentoring young scientists to instill the techniques, knowledge, and skills that have been taught to me and propagate the continued cycle of academic mentorship. Summary of Key Elements of Research Career Development Plan. During the duration of this training program, I will attend regular lab meetings to discuss pertinent data and literature with my group. In addition, I will be expected to present my research to the division at least once a year for criticism and feedback. In order to increase my knowledge in the field of vascular biology and pathology in cardiovascular disease, I will audit several courses at the UNC-CH. I will also attend several seminars both on and off campus to strengthen both my writing and leadership skills. UNC-CH has several weekly and monthly seminars by experts in the field, which I will attend. I will continue to travel to scientific conferences to present my data and interact with the scientific community. Finally, I will meet with my mentor, during the K99 phase, on a weekly basis to discuss my results and the future direction of my research. Project Abstract. Abdominal aortic aneurysm (AAA) affects 5-10% of the male and females over the age of 65 and is the 13th leading cause of death in the United States. AAA, defined as a permanent localized dilation in the arterial wall with a diameter greater than 50% of normal, is an inflammatory disease of the aorta that can result in dissection of the wall, formation of an intramural clot, and rupture of th aorta resulting in almost immediate death in the majority of cases. Importantly, the role of the intramural clot in the etiology of AAA remains poorly explored. We will test the general hypothesis that formation of an intramural clot stabilizes AAAs. Specifically, I will investigate te roles of tissue factor (TF), thrombin, platelets, and protease activated receptors (PARs) in the formation and progression of AAAs. We will utilize the angiotensin II (AngII) LDLr-/- mouse model of AAA. We will use both genetic and pharmacologic approaches to modulate the expression and activity of different proteins and determine the effect on AAA. My proposal is divided into three aims, the first being mentored and the last two being independent. Aim 1 will determine the role of TF in AngII-induced AAA progression and rupture. We hypothesize that decreased TF coagulant activity will reduce clot formation that promotes AAA rupture, and reduced TF and PAR-2 expression by vascular smooth muscle cells (VSMCs) will result in expansion of AAAs due to reduced VSMC migration. Aim 2 will determine the role of thrombin and the downstream effectors fibrinogen and PAR-1 in AAA. We hypothesize that fibrinogen deficiency and anticoagulant therapy will decrease clot formation and lead to an increase in AAA rupture and, that PAR-1 deficiency will increase AAA due to decreased VSMC migration. Aim 3 will examine the role of platelets and the thrombin receptor on platelets (PAR-4) in AAA. We hypothesize that decreased PAR-4-dependent activation on platelets or anti- platelet therapy will reduce clot formation and increase AAA rupture. Together, these studies will increase our understanding of the role of the coagulation cascade, platelets, and PARs in the initiation, progression, and rupture of AAAs. The clinical significance of this work is that use of anti-thrombotic drugs may increase the risk of AAA rupture in patients.