细胞外基质蛋白α3(V)调节细胞代谢机制的研究及对相关代谢性疾病治疗策略的探索

Cell microenvironments play key roles in maintaining normal cell behaviors and, conversely, abnormal “activated” cell microenvironments play key roles in promoting complex diseases such as tumorigenesis and diabetes genesis. Understanding how extracellular matrix (ECM) proteins affect cell behaviors is determining the cell surface moieties with which they interact. We found a new ECM component α3(V) chain that has not previously been implicated in diabetes and cancer biology. α3(V) chains are shown to be bound to the cell surface proteoglycan glypican-1, affecting ability of the latter to act as coreceptor for FGF2 binding, and to contribute to FGF2 signaling and induction of cell proliferation. .The metabolic effects of adipokines, such as adiponectin and leptin, play important role in regulation of gluconeogenesis, glucose glycolysis and lipid catabolism. Levels of the adipokines are inversely correlated with body health or not. Furthermore, these adipokines defects lead to the metabolic derangements that may result in type 2 diabetes, obesity, atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome. Thus, we want to further investigate the unique of model of collagen interaction with cell surfaces, especially function as molecular chaperones in transforming the signals of adipokines such as adiponectin, lectin and resistin, bind to its receptors, thereby initiating intracellular signaling cascades. As the special localization of ECM components in tissues, these studies will be of great importance in generating new markers for prognosis and specious targets for therapeutic interventions.

细胞微环境对于维持细胞正常活动发挥关键性作用，相反，不正常的细胞微环境则会促进复杂性疾病如肿瘤和糖尿病的发生。脂肪细胞因子如adiponectin和leptin等几乎可以影响细胞代谢的每一个过程，体内这些因子的水平直接关乎于人们身体的健康与否。并且这些细胞因子的异常将会导致体内代谢紊乱并进而导致糖尿病、肥胖、动脉粥样硬化乃至癌症等多种代谢性疾病产生。α3(V)是V型胶原纤维的一个亚基，研究发现它对糖尿病及肿瘤发生和成长发挥重要的作用。α3(V)还可以协助FGF2跟它的受体相互作用，从而调节细胞的增值。所以，我们想进一步研究清楚细胞外基质蛋白是否可以协助脂肪细胞因子与其细胞表面的受体相互作用，进而影响细胞内的各种活动。鉴于细胞外基质蛋白的在体内特殊定位，针对它的检测或者是作用药物不需要进入细胞内就能发挥作用，所以，研究清楚它们跟疾病的关系将为相关疾病的诊断和治疗发挥独特的、有效的作用。

课题组继续对α3(V)通过调控胰高血糖素的功能来调控机体的能量代谢的机制进行深入研究，并已经基本完成。和Col5a3敲除小鼠一致的是，发现肌肉组织特异敲除的胰高血糖素受体小鼠具有明显运动耐受缺陷，这个发现打破了人们一直认为的胰高血糖素受体并不存在于肌肉组织，而只是在肝脏组织中发挥重要的功能。同时我们还进一步发现Col5a3-/- 小鼠内plasma Adiponectin下降，并影响小鼠的正常能量代谢及氧消耗水平。研究发现α3(V)蛋白是被高度修饰的，并且进一步发现这些修饰对于α3(V)和adiponectin的相互作用至关重要。从而进一步说明α3（V）对adiponectin功能的影响来调控机体的能量代谢。