糖尿病可导致全身器官的慢性进行性病变及功能缺陷、衰竭，而胃肠道亦不能幸免。我们前期研究表明高糖状态可致肠上皮细胞增殖与分化异常，抑制紧密连接表达并造成屏障受损；该过程与肠道“补漏”分子Syndecan-1 (Sdc1)胞外段Heparan sulfate (HS) 的丢失密切相关，但引起该结果的具体机制、关键调控因素与环节等暂未明确。为此，我们提出“高糖状态经MAPK通路诱发Exostosin (EXT)与Heparanase (HPSE)表达紊乱致使HS链减少，进而启动后续肠道损伤”的研究假设，拟经通路调控、EXT/HPSE/Sdc1 RNA干扰/过表达、基因敲除动物、HS不脱落质粒构建及HS类似物(肝素及改良物)使用、肠屏障结构与功能监测等，验证HS链丢失在糖尿病肠病发病中的核心作用，尝试经“HS链补偿”维护肠道屏障的可行性，为拓展糖尿病并发症的疾病机理认识及防治手段提供新的实验依据。

Diabetes can lead to chronic, progressive, systemic pathological changes, and even functional defect or failure, of which gastrointestinal tract is one of inevitable target organs. In our preliminary study, it is demonstrated that hyperglycemia state has caused abnormalities in proliferation and differentiation of intestinal epithelial cell, down-regulations of tight junction expression, and damages of gut barrier function. These negative feedbacks after hyperglycemia stimulation are closely tied to the extracellular heparan sulfate chains (HS) of Syndecan-1 (Sdc1, the ‘patching’ molecule). However, the concrete mechanism, regulatory factors, and core steps of such preliminary results, are still far from being fully explored. On basis of the above backgrounds, it is supposed that hyperglycemia stimulation induces the imbalance of Exostosin (EXT) and Heparanase (HPSE) via MAPK pathway and then down-regulates HS chains, triggering subsequent damages of gut barrier. Multiple ways, including signal pathway regulation, EXT/HPSE/Sdc1 gene silencing and over-expression, EXT/HPSE gene knockout mice, construction/transfection of mutation plasmids expressing unshedding HS, administration of HS analogues (heparin and its ameliorants), monitor of structures and functions of gut barrier, etc., will be performed. To summarize, the aim of this proposal is to demonstrate the core role of HS losing in diabetic enteropathy and the feasibility of ‘HS compensation’ on maintenance of gut barrier, providing new experimental basis to expand clinical options and strategies for diabetic enteropathy treatments.