Clearance of Apoptotic Cells

这项建议的目的是确定MER在清除细胞凋亡中的生物学相关性 通过巨噬细胞，并描绘出一种解释识别的机制， 巨噬细胞清除凋亡细胞的吞噬和抗炎作用。一个 细胞凋亡识别和更新机制及触发的信号转导途径(S) 对凋亡细胞的作用机制仍知之甚少。假设是Mer/Tyro3/Axl受体酪氨酸激酶 促进凋亡细胞的吞噬作用。我们的初步(体内和体外)研究强烈表明 Mer是一种表达在巨噬细胞上的受体酪氨酸激酶，参与介导 诱导细胞凋亡，并似乎调节抗炎反应。携带Mer突变的小鼠 胞浆信号激酶域(Merkd)具有抑制功能缺陷的巨噬细胞。 促炎细胞因子，如肿瘤坏死因子-α和，在吞噬凋亡细胞方面存在缺陷。 此外，我们推测这种缺陷在临床上与merkd小鼠产生升高的血清有关。 IgM自身抗体和肾脏表现为病理。事实上，越来越多的证据表明，凋亡细胞可以 在自身免疫性疾病的发病机制中起重要作用，而高负担的凋亡细胞可能 为自身抗体的产生提供了重要途径，因为它与系统性红斑狼疮有关。调查 参与识别和清除凋亡细胞的过程可能为控制 炎症和自身免疫性疾病。为了实现这一目标，我们建议对这一过程进行调查 通过新型受体酪氨酸参与体内和体外对凋亡细胞的清除 巨噬细胞上表达的激酶、Ax1、Mer和Tyro3。

The purpose of this proposal is to determine the biological relevance of Mer in the clearance of apoptotic cells by macrophages and to delineate in a mechanism that would account for the recognition, phagocytosis and anti-inflammatory consequence of clearing apoptotic cells by macrophages. A mechanism for recognition and update of apoptotic cells and the signal transduction pathway(s) triggered by apoptotic cells is still poorly understood. The hypothesis is Mer/Tyro3/Axl Receptor Tyrosine Kinases facilitate phagocytosis of apoptotic cells. Our preliminary (in vivo and in vitro) studies strongly suggest that Mer, a receptor tyrosine kinase expressed on macrophages, is involved in mediating the clearance of apoptotic cells and appears to modulate an anti-inflammatory response. Mice with a mutated Mer cytoplasmic signaling kinase domain (merkd) have macrophages that re defective in suppressing pro-inflammatory cytokines such as TNF-a and are defective in phagocytizing apoptotic cells. Furthermore, we presume that this defect is clinically relevant in that merkd mice produce elevated serum IgM autoantibodies and kidney shows pathology. Indeed, evidence is accruing that apoptotic cells can contribute to pathogenesis of autoimmune diseases, and that a high burden of apoptotic cells may provide an important route to autoantibody production as it has been implicated in SLE. Investigating the process involved in recognition and clearance of apoptotic cells may provide insights towards controlling inflammation and autoimmune disorders. Towards this goal, we propose to investigate the process involved in the clearance of apoptotic cells both in vivo and in vitro through novel receptor tyrosine kinases, Axl, Mer, and Tyro3 expressed on macrophages.