Identification of Primate-Specific Regulatory Elements of Cholesterol Homeostasis

灵长类动物特异性胆固醇稳态调节元件的鉴定

• 批准号: 7195980
• 负责人: DARIO BOFFELLI
• 金额: $ 40.25万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-04 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195980
• 关键词: Accounting; Atherosclerosis; Binding Sites; Bioinformatics; Biological Assay; Biology; Cholesterol Homeostasis; Clinical Research; Complement; Conserved Sequence; Cultured Cells; Dietary Cholesterol; Dissection; Elements; Engineering; Enhancers; Evolution; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Targeting; Gene Transfer; Genes; Genomics; Goals; Human; Human Genome; In Vitro; Knock-in Mouse; Lead; Light; Lipids; Mammals; Metabolic; Modeling; Modification; Molecular; Mus; Nuclear Hormone Receptors; Pattern; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Plasma; Positioning Attribute; Primates; Property; Regulation; Regulatory Element; Relative (related person); Reporter; Rodent; Rodent Model; Role; Shadowing (Histology); Stimulus; Structure; Testing; Tissue-Specific Gene Expression; Transgenic Mice; Vertebrates; Work; clinically relevant; comparative; human disease; in vivo; insight; lipid disorder; lipid metabolism; mouse genome; mouse model; nonhuman primate; novel; response; spatiotemporal; tissue culture; transcription factor

DESCRIPTION (provided by applicant): Despite the utility of the mouse and other non-primate vertebrates in studying human lipid metabolism, many human metabolic features are best modeled in primates, particularly our response to dietary cholesterol. The differential regulation of genes involved in cholesterol homeostasis in humans and mice is believed to significantly contribute to differences in response to dietary cholesterol between these species. We have previously shown that sequence comparisons of multiple primate species are successful at identifying functional elements specific to primates and complement traditional sequence comparisons with non-primate mammals, such as between human and mouse. Accordingly, the goal of this proposal is to couple multiple primate sequence comparisons with functional studies to discover primate-specific regulatory elements impacting on lipid metabolism. This will include the analysis of several genes participating in lipid metabolism, with an emphasis on the dissection of the transcriptional network of the nuclear hormone receptor LXR-a and its target genes, crucial regulators of cholesterol homeostasis which appear to have differential regulation in human and mouse. We will: 1) identify and functionally characterize regulatory sequences preferentially conserved in the primate lineage through the comparative analysis of large genomic intervals containing known "lipid" genes; 2) identify and functionally characterize primate specific transcription factor binding sites in both known and computationally predicted regulatory elements shared between primates and non-primate mammals; and 3) investigate the function of primate-specific regulatory sequences on their neighboring human genes in cell culture and in vivo studies and determine their contribution to primate-specific phenotypes. These studies will provide genomically derived insights into the clinically relevant regulation of cholesterol homeostasis and contribute to our understanding of primate-specific responses to environmental stimuli. The mouse, while a valuable model of human diseases such as plasma lipid disorders leading to atherosclerosis, has many differences from human, with the immediate consequence that many drugs first tested successfully in mice fail in later clinical studies in humans. In this proposal, we plan to identify segments of the human genome which determine differences in plasma lipid metabolism between human and mouse. Discovery of this kind of molecular genomic structures will shed new light into the pathogenic mechanisms leading to human lipid disorders, promising to lead to the engineering of better mouse models for this important human disease.

描述（由申请人提供）：尽管小鼠和其他非青春期脊椎动物在研究人脂质代谢方面有实用性，但许多人类代谢特征最好在灵长类动物中建模，尤其是我们对饮食胆固醇的反应。人们认为，人类和小鼠涉及胆固醇稳态涉及的基因的差异调节可显着导致这些物种之间饮食中胆固醇的反应差异。我们以前已经表明，多种灵长类动物物种的序列比较成功地识别了特定于灵长类动物的功能元素，并补充了传统的序列比较与非成群的哺乳动物（例如人和小鼠之间）。因此，该提案的目的是将多个灵长类动物序列与功能研究进行比较，以发现灵长类动物特异性的调节元素，从而影响脂质代谢。这将包括对参与脂质代谢的几种基因的分析，重点是解剖核激素受体LXR-A及其靶基因的转录网络，即胆固醇稳态的关键调节剂，这些调节剂在人和小鼠中似乎具有不同的调节。我们将：1）通过对包含已知“脂质”基因的大型基因组间隔的比较分析来识别和功能表征在灵长类谱系中优先保守的调节序列； 2）在已知和计算预测的调节元件中共享灵长类动物和非成群的哺乳动物之间的灵长类动物特异性转录因子结合位点并在功能上表征和表征。 3）研究灵长类动物特异性调节序列在细胞培养和体内研究中相邻人类基因的功能，并确定它们对灵长类动物特异性表型的贡献。这些研究将为胆固醇稳态的临床相关调节提供基因组得出的见解，并有助于我们对灵长类动物对环境刺激的反应的理解。 小鼠虽然有价值的人类疾病模型，例如导致动脉粥样硬化的血浆脂质疾病，但与人类有许多差异，但直接的结果是，许多在小鼠中成功测试的许多药物在后来的人类临床研究中都在失败。在此提案中，我们计划确定人类基因组的段，这些段确定人与小鼠之间血浆脂质代谢的差异。这种分子基因组结构的发现将为导致人脂质疾病的致病机制提供新的光，并有望为这种重要的人类疾病提供更好的小鼠模型的工程。