Regulation of Acute Graft-versus-Host Disease by Coronins

描述（由申请人提供）：异基因干细胞移植是高危复发性白血病、再生障碍性贫血、先天性骨髓衰竭综合征和复发性或复发性淋巴恶性肿瘤患者的标准治疗。全世界每年进行超过20，000例同种异体移植，证实了其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）发生在30-70%的移植受者中。aGvHD是以靶器官的选择性上皮损伤为特征的综合征，并且由供体骨髓或干细胞接种物中存在的成熟T淋巴细胞介导。虽然GvHD是allo-SCT的一个重要并发症，但它与免疫介导的宿主肿瘤细胞破坏（称为移植物抗白血病（GvL）反应）密切相关。由于allo-SCT仍然是许多疾病的唯一治疗方法，因此必须消除aGvHD的并发症，同时保留GvL反应的有益作用。 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。供体T细胞向初始活化位点的迁移是aGvHD发病机制所需的。细胞外和细胞内组分都负责T细胞的迁移。Coronins（科罗）是一个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。科罗1A主要存在于造血组织中，而科罗1B广泛表达。科罗1A和科罗1B都在T细胞中表达，这使我假设科罗1A或科罗1B的消除将减弱移植受体中的aGvHD。 在本研究训练计划中，我们将首先确定科罗1A或科罗1B缺陷的T细胞对aGvHD的影响。此外，将研究对密切相关的GvL反应的影响。接下来，我们将确定科罗1A和科罗1B如何改变稳态肌动蛋白动力学，导致趋化性和迁移功能障碍。最后，将测定科罗1A或科罗1B缺陷型细胞清除病毒病原体的能力。 遗传学、分子生物学、细胞生物学和免疫学技术的组合将用于确定科罗1A和科罗1B对aGvHD和病毒病原体的影响，并确定冠状蛋白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.