β3整合素含αIIbβ3和αvβ3，血小板无力症（GT）是由ITGA2B或ITGB3基因缺陷引起的出血性疾病，ITGA2B缺失仅影响αIIbβ3介导的血小板功能；ITGB3缺失还可因αvβ3缺失引发非血小板功能异常。β3多态性与血浆甘油三酯（TG）水平有关，敲除αIIb减轻动脉粥样硬化（AS）而敲除β3则增加了AS的发生。我们的前期研究显示，β3敲除小鼠血浆TG增高而脂蛋白脂肪酶（LPL）减低，由此推论β3整合素在脂代谢及AS中起关键作用，但其机制仍待探讨。基于此，本项目拟观察：β3敲除对脂代谢的影响并探讨αvβ3及其活化和相关信号转导对脂代谢的分子调控机制；β3敲除小鼠中特异恢复血小板功能对脂代谢及AS的影响；αIIb或β3缺陷的GT病人的TG水平以评估高脂血症和AS风险。本项目将从新的视角探讨不同基因型GT病人所反映的β3整合素功能对关键生物学过程的调控机制及其病理生理意义和临床价值。

β3 integrins consist of αIIbβ3 and αvβ3. Glanzmann thrombasthenia (GT) is a congenital bleeding disorder caused by mutations in the ITGA2B or ITGB3 genes. ITGA2B deficiency only leads to an absence of αIIbβ3-mediated platelet function, while the ITGB3 deficiency results in the defect of both αIIbβ3 and αvβ3 which may affect, in addition to the platelet function, the αvβ3-regulated non-platelet functions such as lipid metabolism. A previous study showed that the individual polymorphisms of rs5918 of ITGB3 was significantly associated with enhanced triglycerides (TG). Gene manipulation studies further demonstrated that an attenuated atherosclerosis lesion formation in carotid artery and aortic arch was present in the αIIb-/-ApoE-/- mice, indicating that the platelet function is a motivated factor to atherosclerosis lesion formation. In contrast, the β3-/-ApoE-/- and β3-/-LDLR-/- mice exhibited a phenotype of promoted atherosclerosis, indicating that αvβ3 plays a negative regulatory role in atherosclerosis. Our preliminary data also showed that the β3 knock-out mice exhibited an increased TG level along with a decreased lipoprotein lipase (LPL) level in plasma. All these data point to a critical contribution of β3 integrin-mediated biological functions to lipid metabolism and atherogenesis, for which the regulatory mechanisms are yet to be elaborated. The proposed project was designed on the basis of the β3 integrin-deficient mouse model and the platelet lineage-specific recombinant expression technology, in which we seek to examine the effect of β3 knock-out on lipid metabolism and the underlying mechanisms in which αvβ3-regulated signaling may play roles; the effect of the genomic manipulations that specifically rescue the αIIbβ3 expression in platelets in β3-/- mice on lipid metabolism and on atherosclerosis; the plasma level of TG and the risk of hyperlipidemia and AS in GT patients will also be analyzed and evaluated. The implementation of this project will hopefully provide new insights into the precise mechanisms for the β3 integrin-mediated biological functions in regulating the key biological processes and the patho-physiological significance of GT with different genetic defects.