uPA/uPAR and Ro60 in the pathogenesis of congenital heart block

描述(由申请人提供)：本提案描述了一个为期5年的培训计划，该计划建立在Briasouli博士在细胞信号/肿瘤学方面的博士和博士后经验的基础上，以过渡到她开发一个独立的、由壁外资助的、专注于自身免疫介导的组织损伤特别是先天性心脏传导阻滞(CHB)的翻译计划。根据这一目标，Briasouli博士与她的主要赞助人Jill Buyon博士合作制定了一份职业计划。Buyon博士在CHB研究中的翻译专长，她作为国家受影响患者和家属登记处的私人侦探的经验，以及长期的指导记录，将得到两名基础科学家的补充：罗伯特·克兰西博士，他在CHB的发病机制上进行了广泛的工作，以及奥黛丽·伯恩斯坦博士，他是正在研究的UPA/UPAR系统的基础生物学专家。与研究计划相关的科学技能的进一步获得将由TGFbeta专家Daniel Rifkin博士、质谱学专家Thomas Neubert博士和Ro60和细胞凋亡专家Tom Gordon博士提供。免疫学和结构生物学的正式课程将是培训计划的组成部分，并通过参加免疫学和风湿学每周研讨会和杂志俱乐部来加强。交流技能的提高将通过在不同环境中的演讲、进行中的研究、期刊俱乐部、盛大的回合以及向国家会议提交摘要来促进。院校的承诺很强烈，预计会立即晋升为讲师，并迅速晋升为助理教授。Briasouli博士的建议建立在她的新发现的基础上，即uPAR可能在CHB的级联反应中起关键作用，因为它在抗Ro60与凋亡细胞结合后增加了表达/功能，这导致了两种致病事件，从而助长了炎症/纤维化的放大循环。一种是向健康的心肌细胞发出“不要吃我”的信号，试图清除重塑细胞，另一种是产生纤溶酶。目的1探讨抗Ro60抗体利用uPAR抑制细胞凋亡清除的机制。在目标2中，Briasouli博士研究了抗Ro60依赖的纤溶酶原激活增加在触发炎症/纤维化中的后果，重点是潜在的TGF21的激活和巨噬细胞的迁移。在目标3中，概念验证分别通过评估脐带血样本和CHB心脏尸检中的uPAR水平和表达来解决。由于缺乏对这种终生被动获得性自身免疫疾病的预防和治疗，这一提议的健康意义得到了支持。 与公共卫生相关：所有携带抗Ro抗体的妇女都面临着一个令人担忧的前景，即生下一个患有终身心脏病的孩子。到目前为止，还没有预防或治愈这种疾病的方法。这一培训计划将促进一位有前途的基础科学家的发展，他已经在抗Ro抗体可能导致心脏组织损伤的机制方面取得了新的发现。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program which builds on Dr. Briasouli's doctoral and postdoctoral experiences in cell signaling/oncology to transition toward her development of an independent, extramurally-funded, translational program focusing on autoimmune mediated tissue injury in general and congenital heart block (CHB) in particular. In accord with this goal, a career plan has been formulated by Dr. Briasouli in cooperation with her primary sponsor, Dr. Jill Buyon. The translational expertise of Dr. Buyon in the study of CHB, her experience as P.I. of a National Registry of affected patients and families, and longstanding record of mentorship, will be complemented by two basic scientists: Dr. Robert Clancy who has worked extensively on the pathogenesis of CHB and Dr. Audrey Bernstein, an expert in the basic biology of the uPA/uPAR system under study. Further acquisition of scientific skills related to the research plan will be provided by Dr. Daniel Rifkin, an expert in TGFbeta, Dr. Thomas Neubert, an expert in mass spectrometry, and Dr. Tom Gordon, an expert in Ro60 and apoptosis. Formal coursework in immunology and structural biology will be integral to the training program and enhanced by attendance in immunology and rheumatology weekly seminars and journal clubs. Improvement of communication skills will be fostered by presentations in diverse settings; research in progress, journal clubs, grand rounds, and abstract submissions to national meetings. Institutional commitment is strong with anticipation of immediate promotion to Instructor and rapid advancement to Assistant Professor. Dr. Briasouli's proposal builds on her novel finding that uPAR may be critical in the cascade to CHB by virtue of its increased expression/function following anti-Ro60 binding to apoptotic cells, which results in two pathogenic events fueling an amplification loop to inflammation/fibrosis. One is a "don't eat me" signal to healthy cardiocytes attempting clearance of remodeling cells and the other is the generation of plasmin. Aim 1 explores the mechanisms by which anti-Ro60 exploits uPAR to inhibit apoptotic clearance. In Aim 2, Dr. Briasouli investigates the consequences of the anti-Ro60-dependent increase of plasminogen activation in triggering inflammation/fibrosis focusing on activation of latent TGF21 and macrophage migration. In Aim 3, proof of concept is addressed by evaluation of uPAR levels and expression in cord blood samples and autopsies of CHB-hearts, respectively. The health significance of this proposal is supported by the absence of prevention and treatment of this lifelong disease of passively acquired autoimmunity. PUBLIC HEALTH RELEVANCE: All women with anti-Ro antibodies face the alarming prospect of having a child with a lifelong cardiac disease. To date there is no prevention or cure of this disease. This training program will foster the development of a promising basic scientist who has already made a novel discovery regarding the mechanism by which anti-Ro antibodies may cause tissue injury in the heart.