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: 8080333
• 负责人: Zsuzsanna S. Nagy
• 金额: $ 6.19万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8080333
• 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; Therapeutic; Transplantation Tolerance; Uncoupling Agents; Wild Type Mouse; Work; allograft rejection; base; design; novel; novel strategies; 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

迫切需要成功接受移植器官到受损的地方 病人。 T 细胞干扰这个过程；因此，需要新的方法来阻止它们对抗移植物的活动 必须被识别。先前的工作表明，解耦信号传感器的药物制剂 转录激活剂 (Stat)5a 和 StatSb 活性可延长同种异体移植物存活和 Stat5a/b 敲除 小鼠可以表现出移植物耐受性。该项目基于 Stat5a/b 先前调节的假设 未表征的 T 细胞存活基因，包括促凋亡和抗凋亡基因，并试图识别这些新基因 监测它们在移植耐受过程中的诱导。中心假设是 Stat5a/b 的抑制 可以促进同种异体移植物的永久接受，无需与电流和毒性相关的长期治疗 免疫抑制剂。本试点研究的目的是确定小鼠 Stat5a/b 反应基因 T 细胞活性的调节者相信这些新靶点应该会产生新的生物标志物 用于设计新的耐受诱导机制，以实现以下相互关联的目标： 1. 识别导致 T 细胞死亡的 Stat5a/b 靶基因（StatS 依赖基因数据库 S5GD） 使用 Affymetrix 微阵列将 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“接受者与拒绝者”基因数据库 (ARGD) 使用 Affymetrix 微阵列在第 7 天与 Stat5a/b+/+ 小鼠进行比较。 (B) 从第 7 天的 C3H 心脏受体 Stat5a/b-/- 小鼠中识别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. 识别重叠的生物标志物基因数据库（通过比对 S5GD、ARGD 和 GSGD）并验证 通过 Q RT 与耐受小鼠相比，经历器官移植排斥的小鼠中推定的 T 细胞调节基因 PCR（心脏排斥模型）。 与公共卫生的相关性：我们建议重点关注两种对免疫细胞引起排斥反应至关重要的蛋白质 移植器官，即 StatSa 和 StatSb。我们试图了解阻塞的机制 这些蛋白质可以延长移植器官的寿命。应该产生新的战略，以允许 待设计的治疗方法。此外，将更有效地识别新的生物标志物 监测患者对特定治疗的反应