微环境调控Tim-3表达进而影响免疫细胞稳态的机制及意义研究

免疫细胞稳态的异常与多种免疫相关性疾病发生发展的关系近来倍受人们关注。我们前期的研究及相关文献证实：免疫调控分子Tim-3在免疫损伤性疾病如脓毒症的低表达，或在免疫抑制性疾病如肠肿瘤的高表达是导致免疫细胞稳态异常及疾病发生发展的重要因素。微环境影响Tim-3表达进而影响免疫细胞稳态及疾病转归的机制及意义尚不清楚。为深入认识Tim-3在免疫稳态调控中的作用及分子机制，寻求新的疾病干预靶点，本项目拟在前期研究基础上以巨噬细胞为切入点，重点探讨：1）不同微环境调控Tim-3在免疫细胞上不同表达的分子机制；2）Tim-3异常表达影响免疫细胞稳态的细胞内信号传导机制； 3）干预Tim-3通路对免疫损伤性疾病（脓毒症）、免疫抑制性疾病（肠肿瘤）体内免疫细胞稳态的影响及机制，明确将Tim-3作为上述疾病干预靶点的可行性。

Recently scientists pay high attention to the relationship between damaged immune homeostasis and the onset of many immune-related clinical diseases. Our previous data and recent literature showed that Tim-3, an immune regulator, is downregulated in autoimmune conditions such as sepsis, inflammatory bowel disease, while upregulated in immunosuppressive diseases such as colon cancer, and the dysregulated Tim-3 expressions are closely related to the damaged immune homeostasis and diseases onset respectively. However, factors manipulating Tim-3 expression in different microenvironments and mechanisms by which Tim-3 signaling mediates immune homeostasis remain largely unclear. To test the feasibility of using Tim-3 as therapeutic target for treating immune-related diseases, the proposal here will focus on the following projects:①Determining the factors manipulating Tim-3 expression in different microenvironments and making clear the underlying mechanisms.② Making clear the mechanisms especially the signaling cascades by which Tim-3 mediates immune cell homeostasis. ③ Investigating the mechanisms by which Tim-3 interventions reversed immune homeostasis and attenuated diseases progression of autoimmune diseases (sepsis) and of immunosuppressive diseases (colon cancer), making clear whether Tim-3 can be used as a therapeutic target for above immune related diseases.