Patient-Derived Kidney Organoids For Modeling Kidney Injury

用于肾损伤建模的患者肾脏类器官

• 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
• 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

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生科学家 通过基础科学和转化研究，致力于开发肾脏疾病的新疗法， 包括急性肾损伤和同种异体移植排斥。详细了解急性和慢性肾脏病 疾病的发病机制和治疗它们的靶向疗法的进展仍然有限。发展 新的治疗方法由于缺乏全面的体外实验模型而受到阻碍，这些模型完全保留了 肾脏的上皮、基质和免疫成分之间的复杂相互作用。在这部作品中，肯·苏塔， 医学博士，哲学博士，儿科肾脏病医生，科学家，建立在他的专业知识，建立一个病人源性， 除了他的主要导师之外，成人肾脏类器官培养还保留了内源性基质和免疫细胞 博士卡尔文郭的经验与器官从其他组织研究免疫过程和疾病。 首先，使用他建立的成人肾脏类器官作为平台，Aim 1将描述相互作用 在肾毒性损伤中发生于肾上皮和伴随的间质之间， 顺铂这些研究将深入了解损伤后上皮和成纤维细胞的活化和相互作用， 将进一步确定在急性肾损伤向慢性肾损伤的进展中保护性信号与适应不良信号， 肾病这一知识将使新的战略，以破坏纤维化的发展， 促进修复，随后将在成人肾脏类器官中进一步测试。目标2将翻译 利用他的成年肾类器官进行肾移植，利用类器官来模拟同种异体免疫 微环境，关键是在同种异体移植组织内保留宿主免疫细胞。这些类器官将 应用于移植排斥和治疗反应模型，包括免疫功能评估 activation.初步可行性研究将作为未来使用移植的前瞻性研究的原则证明 类器官治疗反应，以告知患者治疗决策。 Sutha博士将受益于斯坦福大学的跨学科环境，沿着资源 并通过儿科部门提供支持。在郭博士的指导下，Vivek Bhalla， Sutha博士和Jonathan Maltzman博士将扩展他在肾脏学和成人肾类器官方面的专业知识 通过开发生物信息学分析和移植免疫学方面的新的互补技能， 成功推进了他的项目。这项训练将使他的肾脏的新应用成为可能 类器官模型来研究肾损伤和移植免疫微环境，最终使他能够 开发和测试新的、有针对性的肾脏疾病疗法。这种方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后产生的结果 目标将作为Sutha博士未来R01研究细胞相互作用和串扰的初步数据， 慢性肾病的进展。