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。这种自身免疫性条件的特征是沿肾小球的免疫复合物积累地下膜（GBM）。是什么触发自身抗体的产生及其对MN器官损伤的贡献仍然不完全理解。因此，对这些病理事件的进一步理解可以实现及时诊断和MN治疗结果的总体改善。我们以前的跨学科蛋白质组学方法将序列蛋白酶HTRA1鉴定为MN中的一种新型自身抗原。在这个“指导”中临床科学家研究职业发展（K23）奖”将实施机械研究确定由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抗原积累的贡献疾病发育将在新开发的MN动物模型中进行研究（AIM 2）。这个为期五年的建议旨在支持候选人从初级物理科学家到在免疫学领先专家，肾脏病学专家的指导下，肾脏病的独立研究者，以及其他相关领域（Haecker博士，Beck和Hageman）。基于候选人的强大临床经验（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）和先前的研究暴露在肾小球疾病中，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，以准备候选人必要沟通和领导能力成为独立调查员。最后，获得充足的资源支持理性的科学研究和教育计划将确保及时成功执行该建议，使候选人能够开始他的职业科学独立道路。