The Serine Protease HTRA1 Antigen: A Gateway to Elucidating Membranous Nephropathy Pathogenesis and the Targeting of Antigen Epitopes

丝氨酸蛋白酶 HTRA1 抗原：阐明膜性肾病发病机制和抗原表位靶向的途径

基本信息

批准号：
10740614
负责人：
Laith Al-Rabadi
金额：
$ 17.65万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-21 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740614
关键词：
Albuminuria Animal Model Animals Antibodies Antibody titer measurement Antigen Targeting Antigen-Antibody Complex Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Automobile Driving Award Basement membrane Binding Biological Assay Blood Brain Bruch&apos s basal membrane structure Career Choice Circulation Clinic Clinical Clinical Research Communication Data Deposition Development Diagnosis Disease Education Electron Microscopy End stage renal failure Endothelial Cells Ensure Epitopes Event Extracellular Matrix Extracellular Matrix Proteins Eye Eye diseases Filtration Foundations Generations Goals Heterophile Antibodies Histologic Homeostasis Human Immune response Immunization Immunize Immunofluorescence Immunologic Immunology In Situ In Vitro Injury Junior Physician Kidney Kidney Diseases Kidney Glomerulus Knockout Mice Knowledge Laboratories Leadership Mediating Membranous Glomerulonephritis Mentors Mentorship Modeling Mus Nephrology Nephrotic Syndrome Organ Oryctolagus cuniculus Pathogenesis Pathogenicity Pathologic Pathology Patients Peptide Hydrolases Peptides Pre-Clinical Model Production Protease Domain Protein Fragment Protein Secretion Proteins Proteinuria Proteomics Renal glomerular disease Research Research Personnel Resources Rodent Running Scientist Serine Protease Serum Site Structure Testing Therapeutic Time Tissues Training Training Activity Transgenic Model Treatment outcome Universities Utah career development chromatin immunoprecipitation clinical development clinically relevant cohort design experience glomerular basement membrane glomerular filtration improved in vivo insight novel overexpression podocyte programs protein function protein protein interaction response skills trypsin-like serine protease

项目摘要

Abstract Primary membranous nephropathy (MN) is a major cause of nephrotic syndrome and kidney diseases. This autoimmune condition is characterized by the accumulation of immune complexes along the glomerular basement membrane (GBM). What triggers autoantibody production and its contribution to organ damage in MN remains incompletely understood. As such, further understanding of these pathological events could enable timely diagnosis and an overall improvement of treatment outcome in MN. Our previous interdisciplinary proteomic approach identified the serine protease HTRA1 as a novel autoantigen in MN. In this “Mentored Clinical Scientist Research Career Development (K23) Award”, mechanistic studies will be implemented to identify the precise pathogenic HTRA1 epitopes targeted by autoantibodies and their impact on HTRA1 protein function (Aim 1). Furthermore, contributions of HTRA1 autoantibodies as well as HTRA1 antigen accumulation to disease development will be investigated in newly developed animal models of MN (Aim 2). This five-year proposal aims to support the transition of the candidate from a junior physician scientist to an independent investigator in nephrology under the mentorship of leading experts in immunology, nephrology, and other relevant fields (Drs. Haecker, Beck, and Hageman). Building upon the candidate’s strong clinical experience (running the glomerular disease clinic at the University of Utah and utilizing biospecimens from the national MN clinical research network of CureGN, ARUP, and Arkana laboratories) and prior research exposure in glomerular disease, various intensive training modules will be designed to refine his scientific knowledge. Career development training will also be implemented to prepare the candidate with the necessary communication and leadership skills to become an independent investigator. Lastly, access to ample resources to support the aforementioned scientific studies and educational programs will ensure a timely successful execution of this proposal, allowing the candidate to begin his career path of scientific independence.

抽象的原发性膜性肾病（MN）是肾病综合征和肾脏疾病的主要原因。这种自身免疫性疾病的特征是免疫复合物沿着肾小球积累基底膜 (GBM) 触发自身抗体产生的因素及其对 MN 器官损伤的影响。因此，对这些病理事件的进一步了解可能有助于实现这一点。 MN 的及时诊断和治疗结果的整体改善。蛋白质组学方法将丝氨酸蛋白酶 HTRA1 鉴定为 MN 中的一种新型自身抗原。临床科学家研究职业发展（K23）奖”，将实施机理研究确定自身抗体靶向的精确致病性 HTRA1 表位及其对 HTRA1 蛋白的影响功能（目标 1）此外，HTRA1 自身抗体以及 HTRA1 抗原积累的贡献。将在新开发的 MN 动物模型中研究对疾病发展的影响（目标 2）。这项为期五年的提案旨在支持候选人从初级医师科学家过渡到在免疫学、肾病学、和其他相关领域（Haecker、Beck 和 Hageman 博士）以候选人强大的临床能力为基础。经验（在犹他大学经营肾小球疾病诊所并利用来自 CureGN、ARUP 和 Arkana 实验室的国家 MN 临床研究网络）和先前的研究曝光在肾小球疾病方面，将设计各种强化培训模块来完善他的科学知识。还将实施职业发展培训，以使候选人具备必要的能力成为独立调查员的沟通和领导能力。支持上述科学研究和教育计划将确保及时成功执行该提案，使候选人能够开始其科学独立的职业道路。