Regulation of Acute Graft-versus-Host Disease by Coronins

描述(申请人提供)：异基因干细胞移植是高危复发白血病、再生障碍性贫血、先天性骨髓衰竭综合征以及复发或复发淋巴系统恶性肿瘤患者的标准治疗方法。全世界每年进行20,000多例同种异体移植，证实了它作为治疗其他致命恶性肿瘤患者的有效性。虽然是一种有效的治疗方法，但急性移植物抗宿主病(AGvHD)在30-70%的移植受者中发生。AGvHD是一种以靶器官选择性上皮损伤为特征的综合征，由供者骨髓或干细胞接种中存在的成熟T淋巴细胞介导。虽然GvHD是allo-SCT的一个重要并发症，但它与宿主肿瘤细胞的免疫介导的破坏密切相关，称为移植物抗白血病(GVL)反应。由于allo-SCT仍然是治疗许多疾病的唯一方法，消除aGvHD的并发症，同时保留GVL反应的有益效果是当务之急。我的长期目标是消除异基因干细胞移植受者的aGvHD，同时保持GVL反应，降低移植受者的发病率和死亡率。供者T细胞向初始激活部位的迁移是aGvHD发病所必需的。T细胞的迁移既有细胞外成分，也有细胞内成分。冠状蛋白(Coronins，CORO)是一类肌动蛋白结合蛋白家族，在细胞运动、迁移和细胞骨架组织中发挥作用。Coro 1A主要在造血组织中发现，而Coro 1B则普遍表达。Coro 1A和Coro 1B都在T细胞中表达，这让我认为消除Coro 1A或Coro 1B会减弱移植受者的aGvHD。在这项研究训练计划中，我们将首先确定Coro 1A或Coro 1B中缺乏的T细胞对aGvHD的影响。此外，还将调查对密切相关的GVL反应的影响。接下来，我们将确定Coro 1A和Coro 1B如何改变导致趋化和迁移功能障碍的稳态肌动蛋白动力学。最后，将确定Coro 1A或Coro 1B缺陷细胞清除病毒病原体的能力。将结合遗传学、分子生物学、细胞生物学和免疫学技术来确定Coro 1A和Coro 1B对aGvHD和病毒病原体的影响，并确定Coronins如何改变稳态肌动蛋白动力学。

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation is a standard treatment for patients with high-risk relapsed leukemia, aplastic anemia, congenital bone marrow failure syndromes, and relapsed or recurrent lymphoid malignancies. Over 20,000 allogeneic transplants are conducted annually worldwide, confirming its effectiveness as a treatment for patients with otherwise lethal malignancies. Although an effective treatment, acute graft-versus-host disease (aGvHD) occurs in 30-70% of transplant recipients. aGvHD is syndrome characterized by selective epithelial damage to target organs and is mediated by mature T lymphocytes present in the donor marrow or stem cell inoculums. While GvHD is a significant complication of allo-SCT it is very closely associated with the immune-mediated destruction of host tumor cells termed the graft-versus- leukemia (GvL) response. As allo-SCT remains the only treatment for many diseases, eliminating complications from aGvHD while retaining the beneficial effects of the GvL response is imperative. My long-term goal is to eliminate aGvHD in allogeneic stem cell transplant recipients while maintaining GvL response, decreasing morbidity and mortality in transplant recipients. Migration of donor T cells to initial sites of activation is required for the pathogenesis of aGvHD. Both extracellular and intracellular components are responsible for the migration of T cells. Coronins (Coro) are a family of actin-binding proteins that function in cell motility, migration, and cytoskeleton organization. Coro 1A is found predominantly in hematopoietic tissue while Coro 1B is ubiquitously expressed. Both Coro 1A and Coro 1B are expressed in T cells leading me to the hypothesis that elimination of Coro 1A or Coro 1B will attenuated aGvHD in transplant recipients. In this research training plan we will first determine the effects of T cells deficient in Coro 1A or Coro 1B on aGvHD. Additionally the effects on the closely related GvL response will be investigated. Next we will determine how Coro 1A and Coro 1B alter steady state actin dynamics that lead to chemotaxis and migration dysfunction. Lastly, the ability of Coro 1A or Coro 1B deficient cells to clear viral pathogens will be determined. A combination of genetics, molecular biology, cell biology and immunology techniques will be used to determine the effects of Coro 1A and Coro 1B on aGvHD and viral pathogens, and determine how Coronins alter steady state actin dynamics.