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

定义 T 细胞在常染色体显性多囊肾病理学中的功能作用

基本信息

批准号：
10323797
负责人：
Katharina Hopp
金额：
$ 3.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323797
关键词：
Adaptive Immune System Advisory Committees Affect Antibodies Autosomal Dominant Polycystic Kidney Bilateral Biological Models CD8-Positive T-Lymphocytes Cancer Biology Cell Count Cell physiology Cells Cellular biology Clinical Clinical Trials Clinical Trials Design Colorado Cost of Illness Cyst Cystic Lesion Cystic kidney Cytometry Data Development Disease Disease Progression End stage renal failure Epithelial Equilibrium FDA approved Future Genetic Genomic Instability Grant Growth Health Image Immune Immune checkpoint inhibitor Immune system Immunologics Immunologist Immunology Immunosuppression Immunotherapy In Vitro Inflammation Inherited Kidney Kidney Diseases Knowledge Malignant Neoplasms Manuscripts Mediating Medical Mendelian disorder Mentors Mentorship Mission Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Outcome PD-1/PD-L1 Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Physicians Play Population Process Proteins Quality of life Recruitment Activity Regulatory T-Lymphocyte Research Research Personnel Research Training Role Scientist Severity of illness Signal Transduction System T cell therapy T-Lymphocyte Techniques Testing Therapeutic Therapeutic Intervention Training Translating Tubular formation Universities Work Writing burden of illness cancer cell cancer clinical trial cancer therapy cancer type career career development clinically relevant design efficacy evaluation genetic approach human disease immune checkpoint improved in vivo innovation macrophage middle age mouse model novel novel therapeutic intervention novel therapeutics pre-clinical programmed cell death ligand 1 programmed cell death protein 1 programs success therapeutic target therapeutically effective therapy development transcriptomics tumor microenvironment

项目摘要

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.

项目概要/摘要此 NIDDK K01 应用程序旨在为 Katharina Hopp 博士提供科学、技术和职业信息培训使她能够转变为一名独立研究者，研究控制常染色体的机制显性多囊肾病 (ADPKD) 囊肿发生。该项目建立在霍普博士在以下领域的专业知识之上： 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。该提案包括在主要指导下的五年培训计划 Raphael Nemenoff 博士是癌症微环境专家，咨询委员会由以下人员组成：卓有成就的免疫学家和 PKD 医生/科学家。该项目将调查 T-的功能作用囊肿发生和进展中的细胞、潜在机制和新的治疗方法。特点 ADPKD 与癌症相似，包括诱导增殖、基因组不稳定性和增加炎。在癌症领域，靶向肿瘤微环境中的 T 细胞已取得临床成功。然而， T 细胞在 PKD 中的功能作用尚不清楚。霍普博士生成的初步数据表明，在 Hopp 博士开发的完善的 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，并且专门针对囊性病变。重要的是，耗尽 CD8+ T 细胞通常具有抗肿瘤作用，可加速疾病进展，突出功能性这些细胞在阻止囊肿进展中的重要性。然而，调节性 T 细胞通常是亲致瘤性，在疾病早期出现，表明不同的 T 细胞亚群可能对囊肿发生。此外，免疫检查点通路的组成部分 PD-L1 和 PD-1 均被小鼠模型和 PKD 患者肾脏切片中显着增加。已针对该途径对多种癌症有治疗效果。因此，该项目的中心假设是相互作用具有囊性微环境/上皮细胞的不同 T 细胞群导致抗和促囊原性效应和靶向 T 细胞代表了 APDKD 的一种新治疗策略。这该项目的具体目标是 (1) 定义 T 细胞亚群在囊肿形成和形成过程中的功能作用进展； (2) 阐明T细胞改变囊性上皮细胞通路的机制；和（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州、丹佛市出色的 PKD 项目、肾脏科和免疫学科。公钥簿该计划已成功将临床前数据转化为临床试验，并有动力将该项目的结果纳入未来的临床试验设计。除了上述目标外，Hopp 博士还将 (1) 开发一种对免疫学和相关新技术/模型系统有丰富的了解； (2) 拓展专业熟练掌握手稿/资助金写作、指导和审查职责； (3) 提交有竞争力的 R01 本 K01 结尾处的应用程序扩展了该应用程序的发现。