smad3对中性粒细胞分化以及功能极化的调控

The neutrophil is the very important cellular compotent of the innate immune system. Many fulminant infection and unusual severe course of infection are due to development or functional defects of these cells. Now, extensive research in the field of neutrophil cell biology revealed that they are not only against invading pathogens, but also involved in the regulation of immune response. The understanding of mechanisms controlling differentiation and function of neutrophils will have important clinical implications and may allow therapeutic manipulation of. these cells. Smad3 is an important receptor activated Smad involved in TGFβ signaling pathway and plays prevalent role in immune regulation. Our previous study of Smad3 knockout mice demonstrated that Smad3 act as an inhibitor of myeloid derived suppressor cells in vivo and Smad3 deficiency in mice lead to high incidence of infectious disease. It suggests that Smad3 is involved in regulation of neutrophil cell biology. In this project, our program is to identify the effect of Smad3 on differentiation and function polarization of neutrophils by using the approach of in vivo transplantation and infectious models, molecular and cellular biology. A better understanding of the regulation of neutrophils by Smad3 will provide a novel clue in the function polarization of neutrophils and therapeutic approach for manipulating TGFβ-Smad3 pathway toward tolerance or immunity in clinics.

中性粒细胞是天然免疫系统的重要组成部分，其缺陷是临床上许多感染性疾病产生和恶化的原因。目前人们认识到它不仅作为效应细胞抗击病原菌入侵，而且具有重要免疫调节作用。因此研究中性粒细胞分化和功能极化的调控有重要临床指导意义。Smad3是TGFβ信号通路下游重要激活型转录因子，参与许多免疫调节过程。基于我们前期对Smad3敲除小鼠的研究发现，Smad3能够调节髓系细胞向髓系抑制性细胞分化，Smad3缺陷小鼠抗感染能力显著降低，提示我们Smad3在调控中性粒细胞发育与功能中发挥作用。本课题将应用多体内外多种实验模型、细胞免疫学、分子生物学等技术手段，系统研究Smad3在中性粒细胞分化、功能极化中的作用及其生理/病理意义，解析Smad3调控中性粒细胞的分子网络。该课题的顺利实施不仅对目前新兴的中性粒细胞功能极化研究领域提供新的线索，并且将为临床开发相关药物提供重要理论基础。