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

摘要 原发性膜性肾病是肾病综合征和肾脏疾病的主要病因。 这种自身免疫性疾病的特征是免疫复合物沿着肾小球的积聚， 基底膜（GBM）。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，进一步了解这些病理事件可以使 及时诊断和全面改善MN的治疗结果。我们以前的跨学科 蛋白质组学方法鉴定丝氨酸蛋白酶HTRA1为MN中的新自身抗原。在这个“指导 临床科学家研究职业发展（K23）奖”，将实施机制研究， 确定自身抗体靶向的确切致病性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动物模型中研究疾病发展（目的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，肾脏学， 和其他相关领域（Haecker，Beck和Hageman博士）。基于候选人强大的临床 经验（运行肾小球疾病诊所在犹他州大学和利用生物标本， CureGN、ARUP和Arkana实验室的国家MN临床研究网络）和既往研究暴露 在肾小球疾病方面，将设计各种强化培训单元，以提高他的科学知识。 还将实施职业发展培训，使候选人具备必要的 沟通和领导能力，成为一名独立的调查员。最后，获得充足的资源 支持上述科学研究和教育计划将确保及时成功 执行这一建议，使候选人开始他的科学独立的职业道路。

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.