Immune dysregulation and kidney disease after hematopoietic cell transplant

造血细胞移植后的免疫失调和肾脏疾病

基本信息

批准号：
9045616
负责人：
Benjamin Lewis Laskin
金额：
$ 17.19万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045616
关键词：
Acute Renal Failure with Renal Papillary Necrosis Albuminuria Allogenic Award BK Virus Biopsy Blood Bone Marrow Transplantation CXCL10 gene CXCL9 gene Calcineurin inhibitor Cell Transplants Cell physiology Child Childhood Chronic Kidney Failure Clinical Clinical Research Cohort Studies Collaborations Collection Complex Complication Creatinine Cytokine Signaling Data Enrollment Environment Enzyme-Linked Immunosorbent Assay Equilibrium Funding Future Glomerular Filtration Rate Goals Health Hematopoietic Hemorrhage Immune Immune response Immune system Immunity Immunocompromised Host Immunologic Markers Immunosuppression Infection Infection prevention Infectious Disease Immunology Inflammation Infusion procedures Injury Instruction Interferons Interleukin-15 Interleukin-6 Intervention Investigation Iohexol K-Series Research Career Programs Kidney Kidney Diseases Kidney Transplantation Kinetics Knowledge Lead Learning Measurable Measures Mediating Mentorship Modeling Monocyte Chemoattractant Protein-1 Monokines Morbidity - disease rate Nephrology Nephrotoxic Organ Organ Transplantation Outcome Patients Pediatric Hospitals Pennsylvania Pharmaceutical Preparations Philadelphia Positioning Attribute Prevention Procedures Proteins Proteinuria Protocols documentation Research Research Design Research Personnel Research Project Grants Risk Risk Factors Sampling Signaling Molecule Solid Specimen Statistical Methods T cell response T-Cell Activation T-Lymphocyte Testing Time Training Translational Research Transplant Recipients Transplantation Transplanted Kidney Complication United States Universities Urine Viral Viremia Virus Virus Diseases Visit allograft rejection base career chemotherapy cohort conditioning design enzyme linked immunospot assay graft vs host disease high risk immunosuppressed improved improved outcome mortality novel novel therapeutic intervention patient oriented research patient population post gamma-globulins prevent prospective reconstitution senior faculty skills skills training translational study urinary

项目摘要

DESCRIPTION (provided by applicant): I am a junior investigator in pediatric nephrology with a strong record of studying kidney disease in hematopoietic cell transplant (HCT) recipients and other immunosuppressed patients. I am committed to an academic career in patient-oriented research with the long-term career goal of leading independent, translational investigations focused on reducing chronic kidney disease (CKD) in HCT and solid organ transplant recipients. My short-term career goal is to hone my skills and training in clinical and translational research by receiving more specialized, formal instruction at the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). Specifically, the objectives of this career development award are: 1) To develop an understanding of immune responses and kidney injury in immunosuppressed children in order to design future interventional studies, 2) To develop the skills necessary to analyze complex longitudinal data by learning advanced statistical methods, and 3) To develop a multi-disciplinary collaboration across two large children's hospitals enabling future translational studies in children post-HCT or solid organ transplant. This training plan will take advantage of an outstanding research environment (CHOP and Penn) and mentorship from senior faculty with expertise in cohort studies, pediatric CKD, kidney transplant, HCT, immunology, and infectious diseases. CKD after pediatric HCT is a significant problem to investigate because 7,000 patients receive an allogeneic HCT each year in the United States, >15% of whom are children. Overall mortality after HCT is unacceptably high-7 years after transplant only about half of patients are alive. CKD, which is a complication in at least 20% of children receiving an HCT, contributes to the high risk of morbidity and mortality after HCT. However, most cases of CKD after HCT are currently considered idiopathic. Identifying novel, modifiable targets for the prevention and treatment of CKD could improve the health and survival of this patient population. We hypothesize that immune dysregulation involving the kidney contributes to CKD after HCT. We will test this hypothesis with two Aims, the first to define the association between BK viral infection, under activation of the immune system, and CKD, and the second to define the association between over activation of the immune system (immune mediated kidney injury) and CKD. These Aims are based on a conceptual model similar to complications of kidney transplant, where impaired immunity leads to BK virus nephropathy and activated immunity causes allograft rejection. To test our hypothesis, we will develop a prospective observational cohort of 150 children undergoing allogeneic HCT at CHOP and CCHMC to systematically measure BK viremia and novel urine markers (CXCL9 and 10) of immune mediated kidney disease during the first year after HCT. This research strategy will provide the evidence for future independent funding proposals designed to decrease morbidity and mortality by preventing, treating, or slowing the progression of CKD in children who are immunosuppressed, including those receiving an HCT or solid organ transplant.

描述（由申请人提供）：我是一名儿科肾病学初级研究员，在研究造血细胞移植（HCT）受者和其他免疫抑制患者的肾脏疾病方面拥有丰富的经验，我致力于与患者一起开展以患者为导向的研究的学术生涯。长期职业目标是领导减少 HCT 和实体器官移植受者慢性肾脏病 (CKD) 的独立、以转化为重点的研究。我的短期职业目标是磨练我在临床和临床方面的技能和培训。具体而言，该职业发展奖的目标是： 1) 加深对接受免疫反应和肾损伤的理解。免疫抑制儿童的研究，以便设计未来的介入研究，2) 通过学习先进的统计方法来培养分析复杂纵向数据所需的技能，以及 3) 在两家大型儿童医院之间开展多学科合作，以实现未来的儿童转化研究该培训计划将利用出色的研究环境（CHOP 和宾夕法尼亚大学）以及具有队列研究、儿科 CKD、肾移植、HCT、免疫学和传染病专业知识的高级教师的指导。儿科 HCT 后的死亡率是一个需要调查的重要问题，因为美国每年有 7,000 名患者接受同种异体 HCT，其中超过 15% 是儿童，仅移植后 7 年，HCT 后的总体死亡率高得令人无法接受。大约一半的患者仍存活，CKD 是至少 20% 接受 HCT 的儿童的并发症，导致 HCT 后发病和死亡的高风险。目前，大多数 HCT 后的 CKD 病例被认为是特发性的。，预防和治疗 CKD 的可修改目标可以改善该患者的健康和生存率，我们勇敢地承认 HCT 后肾脏的免疫失调会导致 CKD。有两个目标，第一个目标是定义免疫系统激活不足的 BK 病毒感染与 CKD 之间的关联，第二个目标是定义免疫系统过度激活（免疫介导的肾损伤）与 CKD 之间的关联。基于类似于肾移植并发症的概念模型，其中免疫受损会导致 BK 病毒肾病，而激活的免疫会导致同种异体移植物排斥。为了检验我们的假设，我们将建立一个由 150 名接受治疗的儿童组成的前瞻性观察队列。 CHOP 和 CCHMC 进行同种异体 HCT，以在 HCT 后的第一年系统地测量 BK 病毒血症和免疫介导的肾脏疾病的新型尿液标志物（CXCL9 和 10）。该研究策略将为未来旨在降低发病率和死亡率的独立资助提案提供证据。通过预防、治疗或减缓免疫抑制儿童（包括接受 HCT 或实体器官移植的儿童）的 CKD 进展。