TWO CANDIDATE GENES ASSOCIATED WITH LDL CHOLESTEROL AND HDL CHOLESTEROL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 该项目将确定羧酸酯酶1（CES 1）和2（CES 2）的变体是否有助于对心脏病易感性的差异。正在研究的假设是，CES 1和CES 2的变异与狒狒血清LDL胆固醇（LDLC）和/或HDL胆固醇（HDLC）浓度和脂蛋白谱的表型变异相关，这种变异影响心脏病易感性的风险。本研究有两个具体的目的：1）确定CES 1和CES 2的多态性，影响LDL C和/或HDL C水平和相关的脂蛋白谱。2)确定编码的氨基酸变体对CES 1和CES 2结构的影响。我们预测，变异体之间观察到的差异将影响CES 1和CES 2结构以及人群中观察到的LDLC和/或HDLC表型，CES 1和CES 2遗传变异体将在关键位置修饰酶结构，影响胆固醇和脂肪酸代谢物的催化活性和结合。鉴定影响胆固醇和脂肪酸代谢的CES 1和CES 2多态性将为预防心脏病提供新的靶点，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.