Targeting Apolipoprotein E4-related Neuropathology

靶向载脂蛋白 E4 相关神经病理学

• 批准号: 6673321
• 负责人: ROBERT W. MAHLEY
• 金额: $ 21.26万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6673321
• 关键词: Alzheimer's disease; alleles; apolipoproteins; conformation; disease /disorder onset; electron spin resonance spectroscopy; fluorescence resonance energy transfer; gene expression; genetic susceptibility; neuropathology

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the most rapidly growing disorders in developed countries. Four million Americans have been diagnosed with this disorder, and as the population grows older and life expectancy increases, the prevalence is expected to double in the next 20 years. Yet at the present time there are no truly effective therapeutics to prevent or even retard the development of AD. The risk factor or susceptibility gene proven to play a major role in AD pathogenesis is the presence of apolipoprotein (apo) E4. ApoE4 is clearly established to increase the occurrence and lower the age of onset of the sporadic and familial forms of late-onset AD. The number of AD patients carrying at least one apoE4 allele ranges from 50-80% in different population studies (the apoE4 allele occurs in approximately 15% of the general population). Studies of the structure and function of apoE have revealed that apoE4 possesses a unique conformation characterized by domain interaction, i.e., arginine 61 in the amino terminus and glutamic acid 255 in the carboxyl terminus interact. ApoE3, the most common apoE isoform, is incapable of domain interaction and has a more open conformation. Many functional properties of apoE4 that distinguish it from apoE3 appear to be modulated by domain interaction. Thus, the hypothesis driving this proposal is that if we could prevent apoE4 from assuming its detrimental structural conformation, we might block the apoE4-related neuropathology. We will use fluorescence resonance energy transfer (FRET) (Specific Aim 1) to identify small molecules capable of preventing domain interaction in apoE4. Screening of chemical libraries in combination with the FRET assay will identify compounds that convert apoE4 to an "apoE3 1ike" molecule structurally and functionally. In addition we will use a fluorescence-release assay to identify small molecules capable of preventing apoE4 destabilization of phospholipid-rich membranes (Specific Aim 2). ApoE4 destabilization of intracellular membranes represents one mechanism whereby apoE4 could be related to neuropathology. Use of these assays in chemical library screening will increase our chances of identifying small molecules ("hits") that act through different mechanisms to modulate apoE4 conformation and related neuropathology. Ultimately, it will be our goal to take "hits" to lead compounds that may give rise to a drug that prevents or retards apoE4-related neuropathology.

描述（由申请人提供）： 阿尔茨海默氏病（AD）是发达国家中增长最快的疾病之一。已有400万美国人被诊断出患有这种疾病，随着人口的增长和预期寿命的增加，预计未来20年的流行率将翻一番。然而，目前尚无真正有效的治疗剂来预防甚至阻碍AD的发展。被证明在AD发病机理中起主要作用的危险因素或敏感性基因是载脂蛋白（APO）E4的存在。明确建立了APOE4，以增加发生的发生，并降低零星和家族形式的晚期AD的发作年龄。在不同人群研究中，携带至少一名APOE4等位基因的AD患者数量为50-80％（APOE4等位基因发生在大约15％的一般人群中）。对APOE的结构和功能的研究表明，APOE4具有以域相互作用为特征的独特构象，即氨基末端中的精氨酸61和羧基末端中的谷氨酸255相互作用。 APOE3是最常见的APOE同工型，无能力具有域相互作用，并且具有更开放的构型。 APOE4的许多功能特性将其与APOE3区分开来似乎是通过域相互作用调节的。因此，推动该提议的假设是，如果我们可以防止APOE4假设其有害的结构构象，我们可能会阻止与APOE4相关的神经病理学。我们将使用荧光共振能量转移（FRET）（特定目标1）来识别能够防止APOE4中域相互作用的小分子。筛选化学文库与FRET分析的结合将识别将APOE4转换为“ APOE3 1ike”分子的化合物，从结构和功能上讲。此外，我们将使用荧光释放测定法来鉴定能够防止富含磷脂富含磷脂的apoE4不稳定的小分子（特定的AIM 2）。 APOE4细胞内膜的稳定是一种机制，APOE4可能与神经病理有关。在化学库筛选中使用这些测定方法将增加我们鉴定通过不同机制来调节APOE4构象和相关神经病理学的小分子（“命中”）的机会。最终，我们的目标是采用“命中”来铅化合物，该化合物可能引起阻止或阻碍与APOE4相关的神经病理学的药物。