SNX27在室管膜细胞分化中的功能和脑积水发生发展过程中的作用

Hydrocephalus is among the most common birth defects, one in every 500 babies born in the world develops hydrocephalus. Hydrocephalus can be classified as non-communicating or communicating. Obstruction of cerebrospinal fluid (CSF) flow is the major cause of non-communicating hydrocephalus. There are various factors that cause abnormal CSF flow, such as the obstruction of cerebral aqueduct, infections, tumors, bleeding or congenital malformation. Moreover, abnormal accumulation of CSF in brain ventricles causes hydrocephalus either by overproduction of CSF or impaired CSF re-absorption. Based on our preliminary observations, our central hypothesis of this proposal is that SNX27 depletion represses ependymal cell differentiation, in turn causes the loss of cilia through disrupting planar cell polarity and Notch signaling pathway. Dysfunction of ependymal cells and cilia leads to impaired CSF re-absorption, and eventually hydrocephalus. In this proposal, we will take advantage of molecular, cell biological and histological techniques and test our hypothesis on a Snx27 knockout mouse model. We will examine the functions of SNX27 in ependymal cell differentiation and ciliogenesis, and elucidate its roles in hydrocephalus. Finally, we will determine whether restoration of SNX27 and its downstream signaling can ameliorate hydrocephalus phenotype of Snx27 knockout mice.

脑积水是一种常见的出生缺陷，每500个婴儿就中有1名患有脑积水。脑积水最常见的病因是脑脊液流动受阻，感染、肿瘤、出血或先天畸形都可能造成脑脊液循环通道受阻。除此之外，脑积水也可能由于脑脊液过剩引起，脑脊液分泌过多或脑脊液吸收障碍都可能引起脑脊液过剩，从而脑内压增加。我们提出假说：SNX27缺失通过影响细胞极性和Notch信号通路抑制室管膜细胞分化和纤毛生成，从而导致脑室中的脑脊液无法被正常吸收，进而造成脑积水。在本项目中，我们将利用Snx27基因敲除动物模型，并结合组织、细胞、分子等技术来验证这一假说。我们还将深入研究SNX27对于室管膜细胞分化和纤毛生成调控的机制，阐明SNX27在脑积水发生发展中的功能。这对于我们更深入地理解脑积水的致病机理，探寻疾病治疗的潜在靶点，具有非常重要的意义。我们还将研究纠正SNX27相关分子通路能否改善Snx27缺失小鼠的脑积水表型。

脑积水是一种常见的出生缺陷，每500个婴儿就中有1名患有脑积水。脑积水最常见的病因是脑脊液流动受阻，感染、肿瘤、出血或先天畸形都可能造成脑脊液循环通道受阻。除此之外，脑积水也可能由于脑脊液过剩引起，脑脊液分泌过多或脑脊液吸收障碍都可能引起脑脊液过剩，从而脑内压增加。本项目中，我们发现SNX27缺失导致小鼠侧脑室边缘室管膜细胞和纤毛缺失从而引起小鼠的先天性脑积水，阐明了SNX27缺失导致脑中神经干细胞产生过度激活的NOTCH蛋白阻止神经前体细胞分化成室管膜细胞。给Snx27缺失孕鼠注射一种γ-分泌酶抑制剂可以明显阻止新生小鼠脑积水的发展并恢复缺失的室管膜细胞和纤毛，进一步证明了γ-分泌酶/NOTCH信号通路参与脑积水的发生发展，并为未来在临床上应用γ-分泌酶抑制剂治疗由室管膜细胞缺陷引起的脑积水提供了一种可能性。此外，我们通过构建小鼠脊髓损伤模型发现SNX27在损伤的脊髓局部表达上调，Snx27基因缺失可通过抑制神经元凋亡及小胶质/巨噬细胞增殖促进小鼠脊髓损伤后功能恢复，为临床上脊髓损伤提供了潜在的治疗靶点。