CD44胞内段介导自噬障碍的机制及在血管内皮细胞衰老中的作用

自噬障碍是诱发血管内皮细胞（VEC）衰老的核心因素，但相关机制远未搞清。我们前期发现CD44的表达伴随VEC衰老不断升高，通过其胞内段（ICD）介导自噬障碍；过表达CD44ICD诱导VEC早衰，激活自噬逆转该现象。此外，CD44ICD调节STAT3和自噬关键调控蛋白PIK3C3的表达并与二者互作。据此我们提出假说：CD44ICD介导的自噬障碍可能是促进VEC衰老的新机制。在此基础上，拟检测增龄条件下CD44ICD对VEC自噬和衰老的调节；明确CD44ICD介导的自噬障碍是否是其诱导VEC衰老的直接原因；解析CD44ICD是否通过STAT3调节PIK3C3的表达、干扰PtdIns3K复合体的装配以及机制；探究CD44ICD介导的自噬障碍是否参与调控病理性VEC衰老。通过本项目的研究，有望揭示CD44ICD介导自噬障碍关联VEC衰老的新机制，为延缓血管衰老、防治心血管疾病提供新的线索和靶点。

Autophagy dysfunction is one of the key factors to induce vascular endothelial cell (VEC) senescence. However, the molecular mechanism underlying autophagy dysfunction and senescence in VECs is still elusive. Previously, we found that the expression of CD44, which mediates autophagy dysfunction through its intracellular domain (ICD), increases with the aging of VECs. Overexpression of CD44ICD induces premature of VECs, a process could be reversed by the activation of autophagy. In addition, we found that CD44ICD modulates the expression of signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the key regulators of autophagy, and interacts with them. Based on these findings, we hypothesize that the autophagy dysfunction mediated by CD44ICD may be a novel mechanism for promoting VEC senescence. To prove this hypothesis, we will further investigate the regulatory role of CD44ICD on VEC autophagy and senescence in the process of aging; determine whether the autophagy dysfunction mediated by CD44ICD is the direct cause for VEC senescence; analyze whether CD44ICD regulates the expression of PIK3C3 through STAT3; investigate whether CD44ICD interferes with the assembly of PtdIns3K complex and elucidate the associated mechanism; explore whether the autophagy dysfunction mediated by CD44ICD is involved in the regulation of pathological VEC senescence. This project is expected to uncover the novel mechanism of CD44ICD-mediated autophagy dysfunction related to VEC senescence, and to provide new clues and targets for delaying vascular aging and preventing cardiovascular diseases.