LDLR Genetics, Splicing and AD Risk

LDLR 遗传学、剪接和 AD 风险

• 批准号: 7150191
• 负责人: Steven Estus
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150191
• 关键词: Alzheimer' s disease; RNA splicing; aging; brain; cholesterol; clinical research; disease /disorder proneness /risk; family genetics; genotype; human genetic material tag; human tissue; immunoprecipitation; lipid metabolism; liver; low density lipoprotein receptor; molecular genetics; protein isoforms; protein localization; protein structure function; receptor expression; single nucleotide polymorphism; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia, i.e., loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels, specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol, e.g., Alzheimer's Disease (AD). Indeed, a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease, apoE is known more widely for its role in cholesterol delivery and homeostasis; apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression, and the haplotypes defined by these functional SNPs, are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence, we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression, 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall, this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds.

描述（由申请人提供）：识别显着改变关键蛋白质功能的遗传变异可以深入了解相关疾病过程和可能的治疗方法。低密度脂蛋白受体 (LDLR) 在这方面非常引人注目，因为 LDLR 突变是家族性高胆固醇血症的主要原因，即单个 LDLR 等位基因的丢失会导致 LDL 胆固醇水平约 100% 增加。尽管 LDLR SNP 及其单倍型与胆固醇水平改变相关，但改变 LDLR 功能的特定 SNP 尚未确定。功能性 LDLR 变异可能有助于了解可能与胆固醇升高相关的疾病，例如阿尔茨海默病 (AD)。事实上，apoE 基因的 apoE4 等位基因是胆固醇和 AD 的一个重要遗传因素。尽管 apoE 与阿尔茨海默病中的淀粉样蛋白 - β (Abeta) 沉积有关，但 apoE 因其在胆固醇输送和体内平衡中的作用而广为人知。 apoE4 通过充当介导脂蛋白摄取的细胞表面受体 LDL 家族的配体，与 LDL 胆固醇升高相关。该提案重点关注这样一个整体假设：调节 LDLR 剪接或表达的 SNP 以及由这些功能性 SNP 定义的单倍型与胆固醇稳态改变和阿尔茨海默氏病相关。因此，我们提出以下具体目标： 1. 评估 LDLR SNP，以确定那些改变 LDLR 剪接和/或表达的 SNP，2. 评估由选择性 LDLR 剪接产生的 LDLR 蛋白的表达和功能。 3. 评估 LDLR 基因型和单倍型与胆固醇稳态和阿尔茨海默病的关联。总体而言，这种重点方法将直接评估 LDLR 多态性调节 LDLR 剪接和表达以增加 LDL 胆固醇和阿尔茨海默病几率的假设。