Novel Specific Ligands for ABeta Oligomers

Aβ 低聚物的新型特异性配体

• 批准号: 7296776
• 负责人: GAL BITAN
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296776
• 关键词: Affect; Affinity; Age; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Antibodies; Appearance; Basic Science; Biological; Biological Assay; Biological Markers; Biology; Biotechnology; Brain; Cells; Cerebrospinal Fluid; Characteristics; Chemicals; Class; Classification; Clinic; Condition; Cultured Cells; DNA Sequence; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Early Diagnosis; Elderly; Immunosorbents; Impaired cognition; In Vitro; Individual; Intervention; Laboratories; Lead; Learning; Libraries; Ligands; Medicine; Memory; Methods; Nature; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Injury; Neurons; Neurotoxins; Pathologic; Patients; Pharmaceutical Preparations; Physiological; Process; Proteins; Research; Rodent; Sampling; Senile Plaques; Specificity; Structure; Symptoms; System; Techniques; Therapeutic; Transgenic Mice; Transgenic Organisms; Work; amyloid formation; aptamer; base; clinical Diagnosis; cost; cross reactivity; crosslink; inhibitor/antagonist; molecular recognition; monomer; mouse model; neurotoxic; neurotoxicity; novel; size; synaptic failure; tool

DESCRIPTION (provided by applicant): This project aims to develop a novel class of molecules that interact specifically and with high affinity with neurotoxic forms of amyloid ¿-protein (A¿), which are believed to cause Alzheimer's disease (AD). To date, AD has no cure and current treatments yield only moderate and temporary relief of symptoms. The clinical diagnosis of AD has sensitivity of ~85%, whereas a definite diagnosis is achieved only post mortem. Effective diagnosis and treatment for AD likely will require sensitive and specific tools for early detection of, and intervention against the neurotoxic processes that lead to development of AD. The new molecules, termed aptamers, will be selected from a library of 10(15) DNA sequences using well established methods that have been shown to yield ligands with high affinity and specificity for a large variety of targets. A difficult problem in the AD field is that the relevant targets are metastable assemblies of A¿, which are difficult to study and isolate. We will overcome this difficulty employing a photochemical cross-linking technique previously developed in our laboratory to stabilize these assemblies. This method enables quantitative purification of individual assemblies. The project includes the following steps: First, aptamers with high affinity and high specificity for neurotoxic A¿ assemblies will be generated. Second, we will develop an aptamer-based diagnostic technique and will use this technique to analyze cerebrospinal fluid samples from patients with AD and from healthy individuals. Third, we will assess the capability of the aptamers to inhibit the neurotoxic effect of A¿ in cultures of neuronal cells as a first step towards development of aptamer-based drugs for treatment of AD. Using this systematic approach, we expect to obtain aptamers with high affinity and high specificity for the metastable, neurotoxic A¿ assemblies and to use these aptamers as novel, mechanism-based tools for AD diagnostics and therapeutics.

描述（由申请人提供）：该项目旨在开发一类新型分子，其与神经毒性形式的淀粉样蛋白特异性且具有高亲和力地相互作用 ¿ - 蛋白质 (A¿)，据信会导致阿尔茨海默氏病 (AD)，迄今为止，AD 无法治愈，目前的治疗方法只能中度和暂时缓解症状，AD 的临床诊断敏感性约为 85%。 AD 的有效诊断和治疗可能需要敏感且特定的工具来早期检测和干预导致 AD 发展的神经毒性过程。 这些被称为适体的新分子将使用成熟的方法从 10(15) 个 DNA 序列库中进行选择，这些方法已被证明可以产生对多种靶标具有高亲和力和特异性的配体，这是 AD 领域的一个难题。是相关目标是 A¿ 的亚稳态组件，这是很难研究和分离的，我们将采用我们实验室先前开发的光化学交联技术来克服这一困难，以稳定这些组件。 该项目包括以下步骤：首先，针对神经毒性A¿具有高亲和力和高特异性的适配体其次，我们将开发一种基于适配体的诊断技术，并将使用该技术来分析 AD 患者和健康个体的脑脊液样本。第三，我们将评估适配体抑制神经毒性作用的能力。 A 的个体作为开发基于适体的 AD 治疗药物的第一步，我们期望获得对亚稳态、神经毒性 A 具有高亲和力和高特异性的适体。组装并使用这些适体作为新型的、基于机制的 AD 诊断和治疗工具。