p75NTR信号调控巨噬细胞表型转换在脓毒症心肌损伤中的作用和机制研究

脓毒症心肌损伤（SIMI)是脓毒症最常见并发症和致死因素之一。脓毒症中心脏巨噬细胞(cMacs)的免疫网络易紊乱，促进SIMI的发生发展。然而重建cMacs稳态的环节及其调控机制尚不清楚。前期工作发现，p75NTR作为促炎信号调控免疫细胞。预实验发现，p75NTR可调控巨噬细胞表型转换，并高表达于SIMI小鼠的促炎型cMacs中。同时，利用巨噬细胞75NTR敲除小鼠建立脓毒症模型并进行RNA-seq检测发现，差异基因显著富集于NF-κB信号通路。故推测脓毒症中巨噬细胞中p75NTR信号上调通过NF-κB通路，驱动巨噬细胞向促炎表型转换，促进SIMI病情发展。本课题拟采用已建立好的巨噬细胞p75NTR基因敲除小鼠，结合原代巨噬细胞和心肌细胞培养，通过体内外实验明确p75NTR对巨噬细胞表型转换及SIMI进程的调控作用，为SIMI防治提供新的潜在靶点。

Sepsis-induced myocardial injury(SIMI) is a common complication of sepsis with high mortality. In sepsis, the immune network of cardiac macrophages (cMacs), which is central mediators of SIMI, is easily disturbed. However, the process and mechanism to recontructe the steady-state of cMacs is unknown. Our preliminary work found that p75NTR is an important signal to promote inflammatory response of immune cells. The preliminary experiments shown that p75NTR signaingl, which highly expressed in cMacs of sepsis mice, would drive phenotypic switch of macrophages towards pro-inflammatory profile. And macrophage specific p75NTR knock-out mice were used in sepsis model, then their macrophage were subjeted to RNA-seq, indicating that deletion of p75NTR changed a variety of genes expression related to the NF-κB pathway.Therefore, the present study speculates that up-regulated p75NTR would drive phenotypic switch of macrophages towards pro-inflammatory profile via NF-κB pathway, which subsequently promote the development of SIMI.To verify this hypothesis, the well-established macrophage specific p75NTR knock-out mice were used to sepsis model in vivo, in combination with primary cell culture of macrophage and cardiomyocytes. Conducting the present project would shed light on the mechanism of SIMI progress from the perspective of macrophages phenotypic switch, and enlighten a potential targets for the prevention and therapy of SIMI.