脑出血后血肿周围区域有大量神经元处于存活-凋亡临界点。研究发现，内质网应激蛋白Herp在机体内环境紊乱时调节细胞自噬向凋亡的转换，对脑出血后血肿周围域神经元的损伤具有调节作用，但具体的机制不明确。课题组研究发现神经营养因子受体p75NTR能够与Herp作用，通过抑制Herp的泛素化降解介导细胞自噬向凋亡的转换，从而加剧脑出血后血肿周围域神经元的损伤。本课题拟在大鼠脑出血模型中检测Herp的表达变化，分析其与血肿周围域神经元存活、自噬、凋亡的关联；体外诱导不同程度脑出血模型中，检测Herp介导自噬向凋亡的转换与p75NTR的相关性以及调节机制；梯度干扰p75NTR的表达，检测Herp何种表达程度时开始介导神经元自噬-凋亡之间的转换；最后在大鼠脑出血模型中靶向干预p75NTR的表达，探索能否通过干预Herp介导的自噬向凋亡的转换促进脑出血后神经功能的恢复，从而为脑出血的治疗提供新的靶点。

Numerous neurons in the vicinity of hematoma undergo dying process following intracerebral hemorrhage (ICH). It is reported that homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp plays an important role in neuronal death after brain injury, probably through the inhibition of autophagy activation. Our previous studies suggest that neurotrophin receptor p75NTR interacts with Herp, and prevents its degradation through ubiquitination. We hereby hypothesize that the expression of both p75NTR and Herp is up-regulated in neurons adjacent to hematoma of ICH, which play a critical role in inducing apoptosis of these neurons. Therefore, manipulation of p75NTR expression would help behavioral recovery following ICH. To test this hypothesis, we will first investigate Herp expression and its association with autophagic formation or neuronal apoptosis in a rat ICH model. Then we will explore the mechanism of Herp in mediating autophagy or neuronal apoptosis in different ER stress models, and its association with p75NTR, and determine the optimal ratio of p75NTR/Herp in inducing the conversion of neuronal autophagy to apoptosis through a gradient interference of p75NTR. Finally, we will manipulate the expression of p75NTR to test the influence of p75NTR/Herp interaction in alleviating the secondary injuries following ICH and promoting behavioral recovery.