TWO CANDIDATE GENES ASSOCIATED WITH LDL CHOLESTEROL AND HDL CHOLESTEROL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目将确定羧酸酯酶1(CES1)和羧酸酯酶2(CES2)的变异是否会导致心脏病易感性的差异。目前正在研究的假设是，CES1和CES2的变异与血清低密度脂蛋白(LDLC)和/或高密度脂蛋白(HDLC)浓度的表型变异以及狒狒的脂蛋白谱有关，这种变异影响心脏病的易感性。本研究有两个具体目的：1)确定CES1和CES2基因多态性对低密度脂蛋白胆固醇和/或高密度脂蛋白胆固醇水平及相关脂蛋白谱的影响。2)确定编码氨基酸变异对CES1和CES2结构的影响。我们预测，不同变异体之间的差异将影响在人群中观察到的CES1和CES2结构以及LDLC和/或HDLC表型，CES1和CES2基因变异体将改变关键位置的酶结构，影响胆固醇和脂肪酸代谢产物的催化活性和结合。识别影响胆固醇和脂肪酸代谢的CES1和CES2基因多态性将为心脏病的预防提供新的靶点，并将有助于靶向治疗心脏病的药物。此外，这些结果将为提交NIH拨款申请提供关键的初步数据，以阐明这些变异影响心脏病特征的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will determine whether variants of carboxylesterase 1 (CES1) and 2 (CES2) contribute to differences in susceptibility towards heart disease. The hypothesis being investigated is that variation in CES1 and CES2 are associated with phenotypic variation in serum LDL cholesterol (LDLC) and/or HDL cholesterol (HDLC) concentrations and lipoprotein profiles in baboons and this variation influences risk of susceptibility to heart disease. This study has two specific aims: 1) To identify polymorphisms in CES1 and CES2 that influence LDLC and/or HDLC levels and associated lipoprotein profiles. 2) To determine the impact of the encoded amino acid variants on CES1 and CES2 structures. We predict that differences observed among variants will influence CES1 and CES2 structure and LDLC and/or HDLC phenotypes observed in the population and that CES1 and CES2 genetic variants will modify enzyme structures in key positions influencing catalytic activity and binding of cholesterol and fatty acid metabolites. Identification of CES1 and CES2 polymorphisms that influence cholesterol and fatty acid metabolism will provide new targets for the prevention of heart disease and will assist in targeting drugs for the treatment of heart disease. Furthermore, these results will provide crucial preliminary data for submission of an NIH grant application to elucidate the mechanisms by which these variants influence heart disease traits.