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

描述（由申请人提供）：该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基础上，过渡到她发展一个独立的，校外资助的转化项目，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）。为了实现这一目标，Briasouli博士与她的主要赞助人Jill Buyon博士合作制定了职业规划。Buyon博士在CHB研究中的翻译专业知识、她作为受影响患者和家庭国家登记处的私人侦探的经验以及长期的指导记录将由两位基础科学家补充：Robert Clancy博士和Audrey Bernstein博士，他们在CHB的发病机制方面进行了广泛的研究，Audrey Bernstein博士是uPA/uPAR系统的基础生物学专家。进一步获得与研究计划相关的科学技能将由tgf β专家Daniel Rifkin博士、质谱专家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成为培训计划的一部分，并通过参加免疫学和风湿病学每周研讨会和期刊俱乐部来加强。通过在不同场合的演讲，将促进沟通技巧的提高；正在进行的研究，期刊俱乐部，大型会议，以及向全国会议提交的摘要。机构承诺强烈，期望立即晋升为讲师，并迅速晋升为助理教授。Briasouli博士的建议建立在她的新发现之上，即uPAR可能在CHB的级联中至关重要，因为在抗ro60与凋亡细胞结合后，uPAR的表达/功能增加，从而导致两种致病事件，促进炎症/纤维化的扩增循环。一种是向试图清除重塑细胞的健康心肌细胞发出“不要吃我”的信号，另一种是产生纤溶蛋白。目的1探讨了anti-Ro60利用uPAR抑制凋亡清除的机制。在Aim 2中，Briasouli博士研究了抗ro60依赖性纤溶酶原激活增加在触发炎症/纤维化中的后果，重点是激活潜伏TGF21和巨噬细胞迁移。在目标3中，分别通过评估脐带血样本和chb心脏尸检中的uPAR水平和表达来证明概念。由于缺乏对这种终身被动获得性自身免疫疾病的预防和治疗，这一建议的健康意义得到了支持。

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.