Tissue Factor & Clot Formation In Abdominal Aortic Aneurysm

组织因子

• 批准号: 8637108
• 负责人: Albert Phillip Owens III
• 金额: $ 7.16万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637108
• 关键词: Abdominal Aortic Aneurysm; Affect; Afibrinogenemia; Age; American; Angiotensin II; Anticoagulant therapy; Aorta; Aortic Diseases; Award; Biology; Blood Platelets; Blood Vessels; Blood coagulation; Caliber; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Coagulants; Coagulation Process; Communities; Complex; Data; Development Plans; Disease; Disease model; Dissection; Educational process of instructing; Elderly; Elements; Etiology; Event; Factor VIIa; Feedback; Female; Fibrinogen; Future; Genetic; Goals; Grant; Inflammatory; Injection of therapeutic agent; Injury; Knowledge; Lead; Leadership; Learning; Life; Literature; Medial; Mentors; Mentorship; National Research Service Awards; PAR-1 Receptor; PAR-2 Receptor; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Phase; Platelet Activation; Principal Investigator; Proteinase-Activated Receptors; Proteins; Publishing; Regimen; Research; Risk; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Scientist; Smooth Muscle Myocytes; System; Techniques; Testing; Thrombin; Thrombin Receptor; Thromboplastin; Thrombosis; Training Programs; Travel; United States; Vascular Diseases; Work; Writing; abstracting; base; career; career development; cell motility; clinically significant; effective therapy; male; meetings; mouse model; mouse protease-activated receptor 4; patient population; post-doctoral training; prevent; programs; protease-activated receptor 4; repaired; role model; skills; symposium; vascular smooth muscle cell migration

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.

描述（由申请人提供）：候选人近期和长期目标概述。我的近期目标是在凝血和血栓领域的专家Nigel Mackman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，我还有很多要向Mackman博士学习。我还想提高我在学术领域作为研究科学家的技能，并发表我目前F32 NRSA资助的剩余项目，如果获得资助，我的资助中提出的K99研究。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，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。和每一位科学家一样，我希望有一天能找到一种有效的治疗方法，减轻无数疾病患者的痛苦，延长生命的质量和时间。此外，我期待着教授和指导年轻的科学家，将他们教给我的技术、知识和技能灌输给他们，并传播学术指导的持续循环。研究职业发展计划的关键要素摘要。在本次培训期间，我将定期参加实验室会议，与我的小组讨论相关数据和文献。此外，我将是