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

有很大的需求成功地接受将移植的器官移植到受损的 有耐心的。T细胞干扰了这一过程；因此，新的方法来阻止它们对移植物的活动 必须被识别出来。以前的工作表明，解偶联信号转导的药物 转录激活因子(Stat)5a和StatSb活性可延长同种异体移植物存活时间和Stat5a/b基因敲除 小鼠可以表现出移植耐受性。该项目基于这样一种假设，即Stat5a/b以前调节 未知的T细胞生存基因，既有促凋亡基因，也有抗凋亡基因，并试图识别这些新基因 在移植耐受过程中监测它们的诱导。中心假设是对Stat5a/b的抑制 可以促进同种异体移植的永久接受，而不需要与当前和毒性相关的慢性治疗 免疫抑制剂。这项初步研究的目的是确定小鼠Stat5a/b反应基因为 T细胞活动的调节者认为这些新的靶点应该会产生新的生物标记物，可以 用于在下列相互关联的目标内设计新的宽容诱导制度： 1.鉴定与T细胞死亡有关的靶基因Stat5a/b(STATS依赖基因数据库S5Gd) 使用Affymetrix微阵列的Stat5a/b-/-小鼠与Stat5a/b+/+小鼠进行比较。 2.(A)从C3H心脏移植Stat5a/b-/-小鼠中鉴定“受体与排斥者”基因数据库(ARGD) 在第7天使用Affymetrix微阵列对比Stat5a/b+/+小鼠。 (B)在第7天从C3H型心脏受体Stat5a/b-/-小鼠中鉴定移植物特异性基因数据库(GSGD) 与使用Affymetrix微阵列的第50天相比。 3.确定重叠的生物标志物基因数据库(通过比对S5GD、ARGD和GSGD)并验证 Q RT法比较器官移植排斥反应小鼠与耐受小鼠的T细胞调控基因 PCR(心脏排斥反应模型)。 与公共健康相关：我们建议重点研究免疫细胞引起排斥反应的两种关键蛋白质 移植器官，即StatSa和StatSb。我们试图了解阻止的机制 这些蛋白质可以延长移植器官的寿命。应该产生新的战略，以实现 治疗方法有待设计。此外，将更有效地识别新的生物标记物 监测病人对某一治疗的反应

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