Role of Stat5a/b in T-cell Survival and Transplantation Tolerance (pilot)

Stat5a/b 在 T 细胞存活和移植耐受中的作用（试验）

• 批准号: 7858093
• 负责人: Zsuzsanna S. Nagy
• 金额: $ 7.19万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858093
• 关键词: Address; Affect; Allografting; Apoptosis; Apoptotic; Biological Markers; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Clonal Deletion; Data; Databases; Family; Future; Gene Targeting; Genes; Graft Rejection; Graft Tolerance; Harvest; Heart; Heart Transplantation; Immune; Immunosuppressive Agents; Knockout Mice; Life; Mediating; Modeling; Monitor; Mus; Organ Transplantation; Patients; Pilot Projects; Process; Proliferating; Proteins; Public Health; Regulator Genes; Role; STAT protein; Signal Transduction; Signaling Protein; T-Lymphocyte; Texas; Therapeutic; Transplantation Tolerance; Uncoupling Agents; Universities; Wild Type Mouse; Work; base; design; novel; novel strategies; programs; response; therapeutic target; transcription factor

There is a significant demand for successful acceptance of transplanted organs into the compromised patient. T cells interfere with this process; therefore, new approaches to block their activity against the graft must be identified. Previous work suggested that pharmacological agents that uncouple signal transducer and activator of transcription (Stat)5a and StatSb activity can prolong allograft survival and Stat5a/b knockout mice can display graft tolerance. This project is based on the hypothesis that Stat5a/b regulates previously uncharacterized T-cell survival genes, both pro- and anti-apoptotic, and seeks to identify these novel genes to monitor their induction during transplantation tolerance. The central hypothesis is that inhibition of Stat5a/b can promote permanent acceptance of allografts without chronic therapy associated with current and toxic immunosuppressants. The objective of this pilot study is to identify murine Stat5a/b responsive genes as regulators of T-cell activity believing that these new targets should result in novel biomarkers that can be used in the design of new tolerance inducing regimes within the following interrelated aims: 1. Identify Stat5a/b target genes (StatS Dependent Gene Database S5GD) responsible for T-cell death from Stat5a/b-/- mice as compared to Stat5a/b+/+ mice using Affymetrix microarrays. 2. (A) Identify "Acceptor vs. Rejecter" Gene Database (ARGD) from C3H heart transplanted Stat5a/b-/- mice vs. Stat5a/b+/+ mice on Day 7 using Affymetrix microarrays. (B) Identify Graft Specific Gene Database (GSGD)from C3H heart acceptor Stat5a/b-/- mice on Day 7 compared to Day 50 using Affymetrix microarrays. 3. Identify the overlapping biomarker gene databases (by aligning S5GD, ARGD and GSGD) and validate putative T-cell regulatory genes in mice undergoing organ graft rejection compared to tolerized mice by Q RT PCR (heart rejection model). Relevance to public health: We propose to focus on two proteins critical for immune cells to cause rejection !of transplanted organs, namely StatSa and StatSb. We seek to understand the mechanism by which blocking these proteins can enhance the life of the transplanted organ. New strategies should result that will allow for therapeutic approaches to be designed. Additionally, novel biomarkers will be identified to more efficiently monitor a patient's response to a given therapy

有一个显着的需求成功接受移植器官到妥协 病人T细胞干扰这一过程;因此，新的方法来阻止它们对移植物的活性 必须加以识别。以前的工作表明，药物，解偶联信号转导 转录激活因子（Stat 5a）和StatSb活性可延长移植物存活和Stat 5a/B敲除 小鼠可以显示移植耐受性。该项目基于Stat 5a/B先前调节的假设 未表征的T细胞存活基因，促凋亡和抗凋亡，并试图确定这些新的基因 以监测它们在移植耐受期间的诱导。中心假设是抑制Stat 5a/B 可以促进同种异体移植物的永久接受，而无需与电流和毒性相关的慢性治疗。 免疫抑制剂本初步研究的目的是鉴定小鼠Stat 5 a/B应答基因， T细胞活性的调节者认为这些新的靶点应该产生新的生物标志物， 在下列相互关联的目标范围内设计新的容忍诱导制度时使用： 1.鉴定负责T细胞死亡的Stat 5 a/B靶基因（StatS依赖性基因数据库S5 GD）， Stat 5a/B-/-小鼠与Stat 5a/B+/+小鼠相比。 2. (A)C3 H心脏移植Stat 5a/B-/-小鼠受体与排斥基因数据库的建立 vs.在第7天，使用Affytron微阵列的Stat 5a/B+/+小鼠。 (B)在第7天从C3 H心脏受体Stat 5a/B-/-小鼠中鉴定移植物特异性基因数据库（GSGD） 与第50天相比，使用Affyssin微阵列。 3.识别重叠的生物标志物基因数据库（通过比对S5 GD、ARGD和GSGD）并验证 通过Q RT比较经历器官移植排斥的小鼠与耐受小鼠中的推定T细胞调节基因 PCR（心脏排斥模型）。 与公共卫生的相关性：我们建议关注两种对免疫细胞引起排斥反应至关重要的蛋白质 !即StatSa和StatSb。我们试图了解阻塞的机制， 这些蛋白质可以提高移植器官的寿命。新的战略应该会产生， 设计治疗方法。此外，将鉴定新的生物标志物，以更有效地 监测病人对给定疗法的反应