细胞分泌的调控及相关肠炎的机理研究

SNAREs are the key protein machinery that mediates membrane fusion. Although extensive research has yielded crucial insights into the function and regulatory mechanism of SNAREs in neurotransmitter release, SNAREs physiological and pathological functions are less understood in tissues other than neuron. The applicant’s laboratory studies the molecular mechanism of intracellular transport and related diseases. In preliminary studies, we have discovered a novel gene mutation (which is named as IB-1) in familial Inflammatory Bowel Disease (IBD) patients. We found that IB-1 directly contributes to SNARE-mediated membrane fusion and is necessary for hormone GLP-1 secretion in cells. We also created IB-1 deficient mice, which may display an IBD phenotype. In the funded program, we will further investigate the molecular mechanism by which IB-1 regulates SNARE function and GLP-1 secretion, and dissect the connection between IB-1 mutation, GLP-1 secretion, and IBD, using a combination of cellular, biochemical, and animal studies. We studies could reveal new non-neuronal function and regulation of SNAREs, and provide novel insights into the pathophysiology of IBD.

SNARE是介导膜融合的最主要的蛋白质机器。尽管SNARE在神经元递质释放中的功能已经非常清楚，其在神经之外其他组织中的功能及调节机制却知之甚少。申请人长期从事细胞内运输与相关疾病分子机制的研究. 目前申请人团队在家族性炎症性肠病的家系中发现了一个全新的突变基因IB-1.前期研究表明IB-1直接参与SNARE介导的膜融合，并控制肠内分泌细胞的荷尔蒙GLP-1的分泌。与野生小鼠相比，IB-1敲除小鼠对于化学诱导的急性肠炎更加敏。申请人将结合细胞生物学、生物化学、小鼠模型、病人样品等进一步研究IB-1调控SNARE的分子机制，确定IB-1突变、GLP-1分泌与炎症性肠病的发生机制。该研究将发现SNARE在非神经元组织中的功能与调节机制，为炎症性肠病的诊断与治疗提供重要理论基础。

细胞分泌是一个非常重要的生物学过程，对于很多细胞和生理学过程都是至关重要的. IB1/SCGN是最近发现的细胞分泌一个的调节因子，在多种组织和细胞内调控荷尔蒙等的分泌，但其分子机制未知。我们综合利用生物化学、结构生物学、细胞生物学及斑马鱼模型等手段阐释了SCGN在细胞分泌和神经发育方面所发挥的重要作用，阐明了SCGN对SNARE蛋白介导的膜融合的调节作用以及对荷尔蒙分泌的调控机制。我们还发现SCGN是一个新型的自闭症易感基因。SCGN的缺失在动物模型上导致催产素降低与免疫反应异常激活。我们的研究为自闭症的发病机制及治疗提供了新线索。