Defining the functional role of T-cells in Autosomal Dominant Polycystic Kidney Disease pathology

项目摘要/摘要 此NIDDK K01应用程序旨在为Katharina Hopp博士提供科学、技术和职业 接受培训，使她能够转变为研究常染色体控制机制的独立研究员 显性多囊肾病(ADPKD)的囊变。该项目建立在霍普博士在 ADPKD的遗传学和细胞生物学，并延长了她在免疫学和微环境方面的培训 这种疾病的某些方面。该提案包括一项为期五年的培训计划，其主要指导是 拉斐尔·涅门诺夫博士，癌症微环境专家，以及由以下成员组成的咨询委员会 有成就的免疫学家和PKD内科医生/科学家。该项目将研究T-蛋白的功能作用。 囊性细胞的发生和发展、潜在的机制和新的治疗方法。的特点 ADPKD与癌症相似，包括诱导增殖、基因组不稳定和增加 发炎。在癌症中，靶向肿瘤微环境中的T细胞已显示出临床上的成功；然而， T细胞在PKD中的功能作用还知之甚少。霍普博士生成的初步数据显示， 在Hopp博士建立的成熟的ADPKD小鼠模型中，不同的T细胞亚群 增加与疾病严重程度的相关性，并定位于囊性病变。重要的是，耗尽了 CD8+T细胞，这通常是抗肿瘤，加快疾病进展，突出功能 这些细胞在阻止囊性病变进展中的重要性。然而，调节性T细胞，通常是促进- 致瘤性，在疾病早期升高，表明不同的T细胞亚群可能对 囊变。此外，免疫检查点途径的组成部分PD-L1和PD-1都是 在小鼠模型和PKD患者肾脏切片中显著增加。以这条路径为目标的 对多种癌症有治疗效果。因此，这个项目的中心假设是相互作用 具有囊性微环境/上皮的不同T细胞群的结果是抗和亲 致囊作用，靶向T细胞是APDKD的一种新的治疗策略。这个 本项目的具体目标是：(1)明确T细胞亚群在囊性形成和形成中的功能作用。 进展；(2)阐明T细胞如何改变囊性上皮细胞通路的机制；以及(3) 评估检查点抑制剂在ADPKD中的疗效。该项目将得到加州大学的支持。 科罗拉多州、丹佛市杰出的PKD项目、肾病科和免疫学系。PKD 该计划已成功地将临床前数据转化为临床试验，并有动力将 这一项目的结果将纳入未来的临床试验设计。除了上述目标外，霍普博士还将(1)制定一项 具有较强的免疫学及相关新技术/模型系统知识；(2)拓展专业知识 精通手稿/助学金写作、指导和评审职责；以及(3)提交竞争性R01 应用程序接近本K01的末尾，在此应用程序的基础上进行扩展。

PROJECT SUMMARY/ABSTRACT This NIDDK K01 application is designed to provide Dr. Katharina Hopp with the scientific, technical, and career training to enable her transition into an independent investigator studying mechanisms controlling Autosomal Dominant Polycystic Kidney Disease (ADPKD) cystogenesis. The project builds on Dr. Hopp's expertise in the genetics and cell biology of ADPKD, and extends her training in the immunological and microenvironmental aspects of this disease. The proposal encompasses a five-year training plan under the primary mentorship of Dr. Raphael Nemenoff, an expert in the cancer microenvironment, and an Advisory Committee comprised of accomplished immunologists and PKD physician/scientists. The project will investigate the functional role of T- cells in cyst initiation and progression, underlying mechanisms, and novel therapeutic approaches. Features of ADPKD parallel those of cancer, including induction of proliferation, genomic instability, and increased inflammation. In cancer, targeting T-cells in the tumor microenvironment has shown clinical success; however, the functional role of T-cells in PKD is poorly understood. Preliminary data generated by Dr. Hopp showed that, in a well-established murine ADPKD mouse model developed by Dr. Hopp, distinct T-cell subpopulations increased correlative to disease severity and localized specifically to cystic lesions. Importantly, depletion of CD8+ T-cell, which are generally anti-tumorgenic, increased disease progression, highlighting the functional importance of these cells in halting cyst progression. However, regulatory T-cells, which are generally pro- tumorgenic, rose early in disease, suggesting that distinct T-cell subpopulations may have opposing effects on cystogenesis. In addition, both PD-L1 and PD-1, components of an immune checkpoint pathway, were significantly increased in the mouse model and PKD patient kidney sections. Targeting this pathway has been therapeutically effective in numerous cancers. Thus the central hypothesis of this project is that interactions of distinct T-cell populations with the cystic microenvironment/epithelium result in both anti- and pro- cystogenic effects, and targeting T-cells represents a novel therapeutic strategy for APDKD. The specific aims of this project are (1) Define the functional role of T-cell subpopulations in cyst initiation and progression; (2) Elucidate the mechanisms how T-cells alter cellular pathways in the cystic epithelium; and (3) Evaluate the efficacy of checkpoint inhibitors in ADPKD. The project will be supported by the University of Colorado, Denver's outstanding PKD Program, the Renal Division, and the Immunology Department. The PKD Program has been successful in translating preclinical data into clinical trials and is motivated to incorporate results of this project into future clinical trial designs. In addition to the above aims, Dr. Hopp will (1) develop a strong knowledge of immunology and related novel technique/model systems; (2) expand her professional proficiencies in manuscript/grant writing, mentoring, and reviewing duties; and (3) submit a competitive R01 application towards the end of this K01 expanding upon findings from this application.