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

uPA/uPAR 和 Ro60 在先天性心脏病发病机制中的作用

• 批准号: 8300102
• 负责人: Paraskevi Briasouli
• 金额: $ 12.71万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300102
• 关键词: Address; Affect; Apoptosis; Apoptotic; Autoimmune Process; Autoimmunity; Autopsy; Binding; Biology; Blood specimen; Cardiac; Cardiac Myocytes; Cells; Child; Communication; Complement; Defect; Development; Disease; Eating; Evaluation; Event; Exhibits; Face; Family; Fetal Heart; Fibrosis; Fostering; Funding; Generations; Goals; Health; Heart; Heart Block; Heart Diseases; Human Development; Immunology; Inflammation; Inflammatory; Injury; Journals; Length; Link; Mass Spectrum Analysis; Mediating; Mentorship; Modeling; Molecular; Molecular Conformation; Neonatal lupus erythematosus; Pathogenesis; Pathologic; Patients; Plasmin; Plasminogen; Positioning Attribute; Prevention; Registries; Research; Resources; Rheumatology; Role; SS-A antibodies; Scientist; Siblings; Signal Transduction; Surface; System; Tissue Stains; Tissues; To autoantigen; Training Programs; Transforming Growth Factor beta; Umbilical Cord Blood; Urokinase; Woman; Work; abstracting; career; experience; extracellular; in utero; instructor; macrophage; meetings; migration; novel; oncology; professor; programs; skills; structural biology

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.

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，该计划以 Briasouli 博士在细胞信号/肿瘤学方面的博士和博士后经验为基础，过渡到她开发一个独立的、外部资助的转化计划，重点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)。根据这一目标，Briasouli 博士与其主要资助者 Jill Buyon 博士合作制定了职业计划。 Buyon 博士在 CHB 研究方面的转化专业知识，她作为 P.I. 的经历。受影响患者和家庭的国家登记册以及长期的指导记录将得到两位基础科学家的补充：罗伯特·克兰西 (Robert Clancy) 博士，他在慢性乙型肝炎的发病机制方面进行了广泛的研究；奥黛丽·伯恩斯坦 (Audrey Bernstein) 博士，正在研究的 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 TGFbeta 专家 Daniel Rifkin 博士、质谱专家 Thomas Neubert 博士以及 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。通过在不同场合进行演讲将促进沟通技巧的提高；正在进行的研究、期刊俱乐部、大型回合以及向国家会议提交摘要。机构承诺强烈，预计将立即晋升为讲师并迅速晋升为助理教授。 Briasouli 博士的提议建立在她的新发现之上，即 uPAR 可能在 CHB 级联反应中至关重要，因为它在抗 Ro60 与凋亡细胞结合后表达/功能增加，从而导致两种致病事件，加剧炎症/纤维化的放大循环。一个是向健康心肌细胞发出“不要吃我”的信号，试图清除重塑细胞，另一个是纤溶酶的产生。目标 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 依赖性纤溶酶原激活增加在引发炎症/纤维化中的后果，重点关注潜在 TGF21 的激活和巨噬细胞迁移。在目标 3 中，通过分别评估脐带血样本和 CHB 心脏尸检中的 uPAR 水平和表达来进行概念验证。由于缺乏对这种被动获得性自身免疫性疾病的终生疾病的预防和治疗，支持了该提案的健康意义。