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

项目总结/摘要 此NIDDK K 01应用程序旨在为Katharina Hopp博士提供科学，技术和职业生涯 培训，使她能够过渡到一个独立的研究者研究机制控制常染色体 显性多囊肾（ADPKD）囊肿形成。该项目建立在霍普博士的专业知识， ADPKD的遗传学和细胞生物学，并扩展了她在免疫学和微环境方面的培训 这种疾病的各个方面。该建议包括一个五年培训计划，主要由以下人员提供指导： 博士癌症微环境专家拉斐尔·内门诺夫和一个咨询委员会， 有成就的免疫学家和PKD医生/科学家。该项目将研究T的功能作用- 细胞在囊肿的发生和发展，潜在的机制，和新的治疗方法。特征 ADPKD与癌症相似，包括诱导增殖，基因组不稳定性和增加 炎症在癌症中，靶向肿瘤微环境中的T细胞已显示出临床成功;然而， T细胞在PKD中的功能作用知之甚少。霍普博士生成的初步数据显示， 在Hopp博士开发的成熟的鼠ADPKD小鼠模型中，不同的T细胞亚群 增加与疾病严重程度相关，并专门局限于囊性病变。重要的是， CD 8 + T细胞，通常是抗肿瘤的，增加了疾病的进展，突出了功能性免疫缺陷。 这些细胞在阻止囊肿进展中的重要性。然而，调节性T细胞，通常是亲， 在疾病早期升高，这表明不同的T细胞亚群可能对肿瘤发生有相反的影响。 囊肿形成此外，PD-L1和PD-1，免疫检查点途径的组分， 在小鼠模型和PKD患者肾切片中显著增加。针对这一途径， 对许多癌症都有效。因此，这个项目的中心假设是， 不同的T细胞群体与囊性微环境/上皮细胞导致抗和促 囊性效应，靶向T细胞代表了APDKD的一种新的治疗策略。的 本项目的具体目标是：（1）确定T细胞亚群在囊肿形成中的功能作用， 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。该项目将得到大学的支持。 科罗拉多，丹佛杰出的PKD计划，肾脏科和免疫科。所述PKD 该计划已成功地将临床前数据转化为临床试验，并有动力将其纳入 将该项目的结果应用于未来的临床试验设计。除了上述目标，霍普博士将（1）制定一个 对免疫学和相关新技术/模型系统有较强的了解;（2）扩展她的专业知识 专业从事手稿/资助写作，指导和审查职责;以及（3）提交竞争性R 01 在本K 01结束时，根据本申请的结果进行扩展。

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.