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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.

项目总结/文摘