Patient-Derived Kidney Organoids For Modeling Kidney Injury

用于肾损伤建模的患者肾脏类器官

基本信息

批准号：
10663719
负责人：
Ken Sutha
金额：
$ 16.75万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663719
关键词：
3-Dimensional Acute Acute Renal Failure with Renal Papillary Necrosis Adult Affect Air Allografting Architecture Basic Science Bioinformatics Biopsy Biopsy Specimen CD3 Antigens Cell Death Cell Survival Cells Childhood Chronic Kidney Failure Cisplatin Complex Culture Techniques Data Development Disease Doctor of Philosophy Environment Epithelial Cells Epithelial-Stromal Communication Epithelium Equilibrium Experimental Models Feasibility Studies Fibroblasts Fibrosis Functional disorder Future Goals Graft Rejection Growth Health Heterogeneity Human Immune Immunosuppression Immunotherapy In Vitro Infiltration Injury Injury to Kidney Intervention Kidney Kidney Diseases Kidney Transplantation Knowledge Laboratories Ligands Liquid substance Mediating Mentors Mentorship Modeling Morphology Muromonab-CD3 Natural regeneration Nephrology Organ Transplantation Organoids Pathogenesis Patients Persons Phenotype Physicians Platelet-Derived Growth Factor Population Process Prospective Studies Research Resolution Resources Sampling Scientist Signal Transduction Structure T-Lymphocyte Techniques Testing Therapeutic Tissues Training Transforming Growth Factor beta Translating Translational Research Transplantation Transplantation Immunology Tubular formation Universities Work allograft rejection career collaborative environment cytokine drug development experience gene panel immune activation immune cell infiltrate immunological diversity improved in vitro Model indexing induced pluripotent stem cell injury and repair innovation insight kidney allograft kidney cell loss of function multiplexed imaging nano-string nephrogenesis nephrotoxicity new therapeutic target novel novel strategies novel therapeutics organoid transplantation pediatric department preservation receptor reconstitution renal damage repaired response single cell analysis single-cell RNA sequencing skills targeted treatment therapeutic development transcriptomics transplant model transplantation therapy treatment response tumor tumor-immune system interactions

项目摘要

Dr. Sutha’s long-term career goal is to be a physician-scientist who improves the lives of his patients through basic science and translational research directed at developing novel therapies for kidney disease, including acute kidney injury and allograft rejection. A detailed understanding of both acute and chronic kidney disease pathogenesis and advancement of targeted therapies to treat them remains limited. Development of novel therapeutics has been hampered by lack of holistic, in vitro experimental models that fully preserve the complex interactions between epithelial, stromal, and immune components of the kidney. In this work, Ken Sutha, MD, PhD, a pediatric nephrology physician-scientist, builds upon his expertise establishing a patient-derived, adult kidney organoid culture preserving endogenous stroma and immune cells, in addition to his primary mentor Dr. Calvin Kuo’s experience with organoids from other tissues for studying immune processes and diseases. First, using his established adult kidney organoids as a platform, Aim 1 will delineate interactions occurring between kidney epithelia and accompanying stroma in the setting of nephrotoxic injury induced by cisplatin. These studies will yield insights into epithelial and fibroblast activation and interactions after injury and will further identify protective versus maladaptive signals in the progression of acute kidney injury to chronic kidney disease. This knowledge will enable the development of novel strategies to disrupt fibrosis while promoting repair, which will subsequently be further tested within adult kidney organoids. Aim 2 will then translate the use of his adult kidney organoids to kidney transplant, using organoids to model the allograft immune microenvironment, critically while preserving host immune cells within allograft tissue. These organoids will then be applied to model transplant rejection and treatment response, including functional assessments of immune activation. Initial feasibility studies will serve as proof of principle for future prospective studies using transplant organoid treatment response to inform patient therapeutic decisions. Dr. Sutha will benefit from the interdisciplinary environment at Stanford University, along with resources and support available to him through the Department of Pediatrics. With mentorship from Drs. Kuo, Vivek Bhalla, and Jonathan Maltzman, Dr. Sutha will expand upon his expertise in nephrology and adult kidney organoid models by developing new, complementary skills in bioinformatic analysis and transplant immunology, critical to successful advancement of his project. This training will enable the novel application of his established kidney organoid model to study kidney injury and the transplant immune microenvironment, eventually enabling him to develop and test new, targeted kidney disease therapies. This approach will be further applied to model other kidney diseases and treatments using biopsy samples, and results generated from the completion of his K08 Aims will serve as preliminary data for Dr. Sutha’s future R01 investigating cellular interactions and crosstalk in the progression of chronic kidney disease.

Sutha 博士的长期职业目标是成为一名改善患者生活的医师科学家通过旨在开发肾脏疾病新疗法的基础科学和转化研究，包括急性肾损伤和同种异体移植排斥对急性和慢性肾的详细了解。疾病的发病机制和治疗这些疾病的靶向治疗的进展仍然有限。由于缺乏完整的体外实验模型来充分保留新的治疗方法，因此受到阻碍肾脏上皮、基质和免疫成分之间复杂的相互作用，Ken Sutha，医学博士、哲学博士是一名儿科肾脏病医师兼科学家，他以自己的专业知识为基础，建立了一种源自患者的、除了他的主要导师之外，还保留了内源性基质和免疫细胞的成人肾脏类器官培养物 Calvin Kuo 博士利用其他组织的类器官来研究免疫过程和疾病的经验。首先，目标 1 将使用他已建立的成人肾脏类器官作为平台来描述相互作用在肾毒性损伤的情况下发生在肾上皮和伴随的基质之间这些研究将深入了解损伤后的上皮细胞和成纤维细胞的激活和相互作用。将进一步确定急性肾损伤进展为慢性肾损伤时的保护性信号与适应不良信号这些知识将有助于开发新的策略来破坏纤维化，同时促进修复，随后将在成人肾脏类器官中进行进一步测试，然后将转化为目标 2。使用他的成年肾脏类器官进行肾移植，使用类器官来模拟同种异体移植免疫微环境，关键是同时保留同种异体移植组织内的宿主免疫细胞。可应用于移植排斥和治疗反应模型，包括免疫功能评估初步可行性研究将作为未来使用移植的前瞻性研究的原理证明。类器官治疗反应可以为患者的治疗决策提供信息。 Sutha 博士将受益于斯坦福大学的跨学科环境以及资源在郭维维克·巴拉 (Vivek Bhalla) 医生的指导下，他得到了儿科的支持。 Sutha 博士和乔纳森·马尔兹曼 (Jonathan Maltzman) 将扩展他在肾脏病学和成人肾脏类器官方面的专业知识通过开发生物信息分析和移植免疫学方面新的、互补的技能来建立模型，这对于他的项目的成功推进将使他所建立的肾脏得到新的应用。研究肾损伤和移植免疫微环境的类器官模型，最终使他能够开发和测试新的、有针对性的肾脏疾病疗法将进一步应用于其他模型。肾脏疾病和使用活检样本的治疗，以及完成 K08 所产生的结果 Aims 将作为 Sutha 博士未来 R01 研究细胞相互作用和串扰的初步数据慢性肾脏病的进展。