Critical Role for Microvasculature in Airway Transplantation

 描述（由申请人提供）：虽然移植可以挽救生命，但慢性排斥反应通常是移植物长期存活的主要障碍。微血管破坏是这一危及生命过程的关键根本原因。目前的免疫抑制方案不足以防止微血管损伤，并且不旨在帮助用健康的血管细胞恢复移植物。在排斥反应期间促进微血管修复是预防实体器官接受者慢性排斥反应的一个有前途的新途径。现在需要理解解释适应性细胞替代的基本机制，以推动该领域的发展。这项竞争性更新R 01赠款的拟议研究旨在解释两个主要过程：1）受体细胞如何被招募来取代微血管中受损的移植内皮细胞，以及2）特定的受体细胞，称为Tie 2单核细胞（TEM），如何也被招募来促进血管生成过程。该项目的重点是缺氧诱导因子（HIF）的作用，这些因子是在排斥反应期间对低组织氧做出反应的关键转录因子，此时受损的微血管停止灌注移植组织并促进纤维化重塑。具体目标1将确定受体细胞如何响应HIF信号，差异参与移植微血管修复。第一个子目标评估内皮谱系细胞的贡献以及HIF-1a或HIF-2a的功能获得和丧失如何影响受体细胞投资微血管。第二个子目标评估了非内皮细胞（如间充质干细胞）的贡献，并类似地评估了HIF-1a表达如何影响其整合到受损血管中的能力。特异性目的2将确定HIF-1a和HIF-2a在TEM迁移和血管生成中的作用。四个子目标评估HIF亚型在一系列体内和体外研究中的作用，这些研究涉及上调TEM中HIF的产生是否通过前列腺素E2的产生促进血管生成。

 DESCRIPTION (provided by applicant): While transplantation can be lifesaving, chronic rejection is frequently a major obstacle to long-term graft survival. Microvascular destruction is critical root-cause underlying this life-threatening process. Current immunosuppressive regimens do not sufficiently protect against microvascular injury and are not designed to help restore the transplant with healthy vascular cells. Promoting microvascular repair during rejection episodes is a promising new avenue for preventing chronic rejection in solid organ recipients. An understanding of the basic mechanisms explaining adaptive cell replacement is now needed to move the field forward. The proposed studies of this competitive renewal R01 grant are designed to explain two major processes: 1) how recipient cells are recruited to replace damaged transplant endothelial cells in microvessels and 2) how particular recipient cells, called Tie2 monocytes (TEMs), are also recruited to facilitate the angiogenic process. The project focuses on the role of the hypoxia-inducible factors (HIFs) that are the key transcription factors responsive to low tissue oxygen during rejection episodes when injured microvessels stop perfusing the transplanted tissues and fibrotic remodeling is promoted. Specific Aim 1 will determine how recipient cells, responding to HIF signals, differentially participate in transplant microvascular repair. The first subaim evaluates the contribution of endothelial-lineage cells and how a gain- and loss-of-function of HIF-1a or HIF-2a affects recipient cells investing into microvessels. The second subaim evaluates the contribution of non-endothelial cells, such as mesenchymal stem cells, and similarly evaluates how HIF-1a expression affects their ability to incorporate into damaged vessels. Specific Aim 2 will determine the role of HIF-1a and HIF-2a on TEM migration and angiogenesis. Four subaims evaluate the role of HIF isoforms in a series of in vivo and in vitro studies that address whether upregulating HIF production in TEMs promotes angiogenesis via the production of prostaglandin E2.