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

描述（由申请人提供）：本提案描述了一项为期5年的培训计划，该计划基于Briasouli博士在细胞信号传导/肿瘤学方面的博士和博士后经验，旨在过渡到她开发的独立的、壁外资助的转化计划，该计划主要关注自身免疫介导的组织损伤，特别是先天性心脏传导阻滞（CHB）。雅阁这一目标，Briasouli博士与她的主要赞助人Jill Buyon博士合作制定了一项职业计划。Buyon博士在CHB研究中的翻译专业知识，她作为P.I.两名基础科学家将对受影响患者和家庭的国家登记处和长期指导记录进行补充：Robert Clancy博士，他在CHB的发病机制方面进行了广泛的研究; Audrey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取将由TGF β专家丹尼尔里夫金博士、质谱专家托马斯诺伊伯特博士和Ro 60和细胞凋亡专家汤姆戈登博士提供。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流变学每周研讨会和期刊俱乐部来加强。沟通技能的提高将通过在不同环境中的演讲来促进;正在进行的研究，期刊俱乐部，大圆桌会议和向国家会议提交的摘要。机构的承诺是强烈的预期立即晋升为讲师和快速晋升为助理教授。Briasouli博士的建议建立在她的新发现的基础上，即uPAR可能在CHB的级联反应中至关重要，因为在抗Ro 60与凋亡细胞结合后，其表达/功能增加，这导致两个致病事件，助长了炎症/纤维化的放大循环。一个是“不要吃我”的信号，健康的心脏细胞试图清除重塑细胞，另一个是纤溶酶的产生。目的1探讨抗Ro 60抗体利用uPAR抑制凋亡清除的机制。在目标2中，Briasouli博士研究了纤溶酶原激活的抗Ro 60依赖性增加在触发炎症/纤维化中的后果，重点是潜在TGF 21和巨噬细胞迁移的激活。在目的3中，通过分别评价脐带血样品和CHB心脏尸检中的uPAR水平和表达来解决概念证明。这一建议的健康意义得到了缺乏预防和治疗这种被动获得性自身免疫性终身疾病的支持。

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.