Clearance of Apoptotic Cells

超出提供的空间。本研究的目的是确定Mer在巨噬细胞清除凋亡细胞中的生物学意义，并阐明巨噬细胞清除凋亡细胞的识别、吞噬和抗炎作用的机制。细胞凋亡的识别和更新机制以及由细胞凋亡引发的信号转导通路(S)仍然知之甚少。假设是Mer/Tyro3/Axl受体酪氨酸激酶促进了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，巨噬细胞上表达的受体酪氨酸激酶Mer参与了凋亡细胞的清除，并似乎调节了抗炎反应。携带Mer胞浆信号激活域(Merkd)突变的小鼠，其巨噬细胞在抑制促炎细胞因子(如肿瘤坏死因子-a)和吞噬凋亡细胞方面存在缺陷。此外，我们推测这种缺陷与临床相关，因为MERKD小鼠产生升高的血清IgM自身抗体，肾脏表现为病理。事实上，越来越多的证据表明，凋亡细胞可以促进自身免疫性疾病的发病，而且大量的凋亡细胞可能提供了一条产生自身抗体的重要途径，因为它与系统性红斑狼疮有关。研究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提供见解。为了达到这一目标，我们建议通过巨噬细胞上表达的新型受体酪氨酸激酶Ax1、Mer和Tyro3来研究体内和体外清除凋亡细胞的过程。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================