Predictive biomarkers of treatment response in kidney transplant rejection

肾移植排斥反应治疗反应的预测生物标志物

基本信息

批准号：
10534089
负责人：
Shana M. Coley
金额：
$ 13.54万
依托单位：
NEPHROPATHOLOGY ASSOCIATES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-04 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534089
关键词：
Activities of Daily Living Acute Address Aftercare Allografting Animal Model Archives Behavior Biological Biological Assay Biological Markers Biological Models Biopsy Biopsy Specimen Cells Cellular biology Characteristics Chronic Disease Clinical Clinical Data Clinical Protocols Collaborations Contracts Data Development Diagnosis Diagnostic Dialysis procedure Epidemiology Extracellular Matrix Failure Formalin Gene Expression Profile Genes Goals Graft Rejection Grain Hand Health Care Costs Heterogeneity Histologic Human Immunofluorescence Microscopy Immunologics Immunosuppression In Situ Industry Inflammation Kidney Kidney Transplantation Knowledge Life Longevity Machine Learning Malignant Neoplasms Mediating Medical Records Methods Molecular Profiling Nephrology Outcome Paraffin Embedding Pathway interactions Patient-Focused Outcomes Patients Pattern Phenotype Pilot Projects Population Quality of life Residual state Resistance Resources Retrospective cohort Risk Savings Selection for Treatments Steroid Resistance Steroids T memory cell T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Time TimeLine Tissue-Specific Gene Expression Tissues Transplantation Treatment Failure Treatment outcome Universities analytical method base bioinformatics pipeline biomarker identification cell behavior clinical diagnostics cohort design differential expression digital imaging effective therapy graft function health economics high dimensionality human tissue image processing improved infection risk kidney allograft migration new therapeutic target novel novel strategies outcome prediction patient population patient stratification predicting response predictive marker predictive signature preservation recruit response risk prediction model statistics targeted treatment therapy resistant transcriptome transcriptome sequencing treatment response

项目摘要

PROJECT SUMMARY The overall purpose of this proposal is to develop predictive biomarkers of treatment outcome in kidney transplant rejection, specifically in T-cell mediated rejection (TCMR), as the response to treatment can be variable, is currently not predictable by clinical diagnostics nor understood from a mechanistic sense, and even partial treatment failure is associated with shortened graft longevity. In each aim, we make use of residual diagnostic biopsy samples with paired richly-detailed clinical data and timelines including treatments, graft functional responses and outcomes. In this manner, we track along the clinical timeline of TCMR, with each aim addressing an unsolved clinical problem in the field. Through the same approach, experimental data from this unique “model system” of tissue inflammation studied over time provides a rich discovery set for understanding tissue-resident T cell behavior in the human kidney. Aim 1 looks at the whole transcriptome profiles of initial acute episodes of TCMR prior to treatment, to identify a gene expression signature predictive of resistance/sensitivity to standard therapies for rejection. When treatment fails, grafts frequently contain residual T cell infiltrates, but the causal connection between these cells and long- term outcome is unclear. For example, residual infiltrates may represent (i) contracting/egressing populations of T cells effectively treated, (ii) newly recruited T cells mounting a fresh rejection response where repeat therapy may be prudent, or (iii) scant memory T cells with established tissue posts and capable of inciting repeat inflammation. Therefore, in Aim 2, we focus on post-treatment biopsies of treatment failure, characterizing multiple spatio-phenotypic aspects of the T cell infiltrate by high dimensional immunofluorescence microscopy with digital image processing and quantitative spatial analysis, to determine which functional phenotypic T cell subsets in which specific tissue niches, correlate with poor graft outcomes. These complementary but independent aims will be achieved through established cross-disciplinary collaborations and with partial industry support.

项目摘要该提案的总体目的是开发肾脏移植中治疗结果的预测生物标志物排斥反应，特别是在T细胞介导的排斥反应（TCMR）中，因为对治疗的反应可能是可变的，是目前无法通过临床诊断来预测，也无法从机械意义上理解，甚至部分治疗失败与缩短的移植物寿命有关。在每个目标中，我们都会利用残留的诊断活检样本和配对的丰富详细临床数据和时间表，包括治疗，移植功能反应和结果。通过这种方式，我们跟踪 TCMR的临床时间表，每个目标都解决了该领域未解决的临床问题。通过相同方法，随着时间的推移，来自组织注入研究的独特“模型系统”的实验数据提供了丰富的发现，用于理解人肾脏中的组织T细胞行为。 AIM 1查看治疗前TCMR初始急性发作的整个转录组曲线，以识别基因表达信号预测对排斥的标准疗法的抗性/敏感性。治疗时失败，移植物经常包含残留的T细胞浸润，但是这些细胞与长期的因果关系术语结果尚不清楚。例如，残留浸润可能表示（i）收缩/出口的种群 T细胞有效治疗，（ii）新募集的T细胞安装了新的排斥反应，重复治疗可能是谨慎的，或（iii）具有已建立组织柱的记忆T细胞，能够煽动重复炎。因此，在AIM 2中，我们专注于治疗失败的治疗后活检，表征高尺寸免疫荧光显微镜浸润T细胞的多个空间 - 表型方面通过数字图像处理和定量空间分析，以确定哪种功能表型T细胞特定组织壁细分市场的子集与较差的移植结局相关。这些完整，但是独立目标将通过已建立的跨学科合作和部分行业实现支持。