钙离子介导mTOR调控T淋巴细胞亚群功能失衡在慢性非细菌性前列腺炎发病机制研究

Chronic nonbacterial prostatitis(CNP) has become a common disease in young man, it has a significant morbidity, low cure rate and easy recurrence, and severely threatens male health and life quality, but the mechnaism of CNP remains unknown. Some studies indicate that T lymphocyte subsets cells are play key role in CNP, and T lymphocyte subsets cells are relate with electrophysiological activity of Ca2+ and mTOR pathway. mTOR is key role in immunity and inflammation, and regulated by Ca2+,and the mechnaism remains unknown. We previously study show that the mechanism of chronic nonbacterial prostatitis is associated with Ca2+ channel, and mTOR pathway promote the development of CNP, it suggest that Ca2+ mediate mTOR regulate the function imbalance of T lymphocyte subsets cells may be the mechnaism of CNP. So, we will intend to study the function of T lymphocyte subsets cells and relevant cytokines, applying the animal models of CNP; exploring to the T lymphocyte subsets cells in CNP with Ca2+ and mTOR; investigating the mechnaisms Ca2+ mediate mTOR regulate the function imbalance of T lymphocyte subsets cells in CNP;revaling its mechanisms of the key molecular and regulatory net, it provide the new theoretical basis of mechanisms in CNP, and provide the new strategies and targets in CNP

慢性非细菌性前列腺炎(CNP)是好发于男性青壮年的常见病，该病患病率高，治愈率低，且易复发，严重危害患者身心健康，发病机制尚不明确。研究表明，T淋巴细胞亚群在CNP的发病中起关键作用，其功能与Ca2+电生理活动和mTOR通路密切相关。mTOR是机体免疫和炎症的关键调控中枢，其功能受Ca2+的信号调节，但具体机制尚不清楚。本课题组前期发现Ca2+与CNP发病机制密切相关，且mTOR通路促进CNP的发生发展，提示Ca2+通过mTOR途径调控T淋巴细胞亚群失衡是CNP的可能发病机制。本项目拟借助CNP大鼠模型，研究CNP中T淋巴细胞亚群功能及相关细胞因子变化；探讨Ca2+和mTOR通路调控T淋巴细胞亚群在CNP发病中的作用；研究Ca2+通过mTOR途径对CNP中T淋巴细胞亚群失衡调控机制；揭示CNP发病机制的调控网络和关键分子。为其发病机制提供新的理论依据，为CNP防治提供新的策略与作用靶点。

慢性非细菌性前列腺炎(CNP)是好发于男性青壮年的常见病，该病患病率高，治愈率低， 且易复发，严重危害患者身心健康，到目前为止，CNP的发病机制仍不明确。本研究从分子、细胞、动物、临床等多层次探索了CNP的可能发病机制。首先，课题组通过建立慢性前列腺炎动物模型（EAP），在动物及临床水平上发现Th1、Th17在CNP发病过程中显著增加及Th1/Th2、Th17/Treg比例的失衡，并在EAP小鼠前列腺组织中发现Akt、mTOR相关蛋白的表达升高。并进一步在前列腺组织标本中发现了mTOR通路中相关蛋白的表达差异。通过抑制小鼠体内CaMK4、Akt、mTOR通路可明显降低EAP小鼠脾脏中Th17的分化比例，从而缓解EAP小鼠前列腺组织炎症的严重程度，最终发现在EAP中Ca2+依赖的CaMK4通过Akt/mTOR信号通路促进了Th17分化。我们还发现肠道菌群失调参与EAP诱导的抑郁行为，并可能通过肠脑轴途径增加海马小胶质细胞和星型胶质细胞的激活，促进TNF-α、IL-1β等炎症因子的释放，形成神经炎症，进一步介导谷氨酸和五羟色胺神经递质系统异常，导致抑郁的发生。酒精可通过激活NLRP3炎症小体通路加重EAP小鼠慢性前列腺炎症，而不是直接诱导引起前列腺炎。此外，我们还发现褪黑素可通过抑制NLRP3炎症小体的激活从而缓解EAP小鼠慢性前列腺炎症；HA合成酶抑制剂（4-MU）可通过抑制Th1的分化缓解EAP小鼠慢性前列腺炎症及毛萼乙素可通过影响NF-κB、PI3K/Akt/mTOR通路缓解EAP小鼠慢性前列腺炎症。本研究初步阐明了慢性前列腺炎发生与T细胞比例失衡、NLRP3炎症小体的关系及其分子机制，为慢性前列腺炎的诊治提供了一种新的思路和可能的治疗靶点。

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