Tissue Factor & Clot Formation In Abdominal Aortic Aneurysm

组织因子

• 批准号: 8425696
• 负责人: Albert Phillip Owens III
• 金额: $ 7万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425696
• 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）：候选人立即和长期目标的摘要。我的直接目标是在凝血和血栓形成领域的专家Nigel Mackman博士的指导下继续进行博士后培训。我仍然有很多关于麦克曼博士关于组织因子在血管疾病中的功能的知识。我还想提高我作为学术领域的研究科学家的技能，并从当前的F32 NRSA赠款中发布剩余的项目，并在我的赠款中提出的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，其研究重点是理解心血管疾病的起始和进展，专注于腹部主动脉瘤。像其他每个科学家一样，我希望有一天能找到一种有效的治疗方法，可以减轻众多患有疾病的患者的痛苦并延长生命的质量和持续时间。此外，我期待教学和指导年轻的科学家，以灌输已教给我的技术，知识和技能，并传播持续的学术指导周期。研究职业发展计划的关键要素的摘要。在此培训计划期间，我将参加定期的实验室会议，与我的小组讨论相关的数据和文献。此外，我会 希望每年至少向该部门提出我的研究，以征询批评和反馈。为了提高我在心血管疾病中血管生物学和病理学领域的了解，我将在UNC-CH审核几门课程。我还将参加校园内外的几个研讨会，以增强我的写作和领导能力。 UNC-CH由该领域的专家举办几次每周和每月的研讨会，我将参加。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，我将每周在K99阶段与导师会面，以讨论我的结果和研究的未来方向。项目摘要。腹主动脉瘤（AAA）影响了65岁以上男性和女性的5-10％，是美国第13个主要死亡原因。 AAA被定义为直径大于正常的50％的动脉壁中的永久性局部扩张，是主动脉的炎症性疾病，可能导致壁的解剖，形成壁内凝块的形成以及主动脉的破裂，导致病例几乎立即死亡。重要的是，壁内凝块在AAA病因中的作用仍然受到探讨。 我们将检验一个普遍的假设，即形成壁内凝块会稳定AAAS。具体而言，我将研究组织因子（TF），凝血酶，血小板和蛋白酶活化受体（PAR）的作用，在AAA的形成和进展中。 我们将利用AAA的血管紧张素II（Angii）LDLR - / - 小鼠模型。我们将使用遗传和药理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，第一个目标是指导的，最后两个是独立的。 AIM 1将确定TF在ANGII诱导的AAA进展和破裂中的作用。我们假设降低的TF凝结活性将减少凝块形成，从而促进AAA破裂，而血管平滑肌细胞（VSMC）降低TF和PAR-2表达将导致由于VSMC迁移的减少，AAAS的扩大。 AIM 2将确定凝血酶和下游效应子纤维蛋白原和PAR-1在AAA中的作用。我们假设纤维蛋白原缺乏症和抗凝治疗将减少凝块的形成并导致AAA破裂的增加，并且由于VSMC迁移降低，PAR-1缺乏症将增加AAA。 AIM 3将检查AAA中血小板和凝血酶受体在血小板（PAR-4）中的作用。我们假设在血小板或抗血小板疗法上依赖4杆4的依赖性激活将减少凝块形成并增加AAA破裂。总之，这些研究将加深我们对凝血级联，血小板和PAR在AAAS的启动，进展和破裂中的作用的理解。这项工作的临床意义是使用 抗栓性药物可能会增加患者AAA破裂的风险。