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（由应用提供）：该项目旨在开发一种新型的分子，这些分子具有特定相互作用，并且与淀粉样蛋白的神经毒性形式高亲和力，据信引起阿尔茨海默氏病（AD）。迄今为止，AD无法治愈，目前的治疗只会产生适度和暂时缓解症状。 AD的临床诊断的灵敏度约为85％，而在验尸中仅实现了定义的诊断。有效的AD诊断和治疗可能需要敏感和特定的工具，以便早期检测以及针对导致AD发展的神经毒性过程的干预。 新的分子（称为适体）将使用已建立的良好方法从10（15）个DNA序列的库中选择，这些方法已显示出对各种靶标产生高亲和力和特异性的配体。广告字段中一个困难的问题是，相关目标是A¿的可稳定组件，很难研究和分离。我们将使用以前在实验室中开发的光化学交联技术来克服这一困难，以稳定这些组件。此方法可以定量纯化单个组件。 该项目包括以下步骤：首先，将生成具有高亲和力和高特异性神经毒性A的适体。其次，我们将开发一种基于APATMER的诊断技术，并将使用此技术来分析来自AD和健康个体患者的脑脊液样品。第三，我们将评估适体在神经元细胞培养物中的神经毒性作用的能力，这是开发基于ATAMER的药物以治疗AD的第一步。使用这种系统的方法，我们期望获得具有高亲和力和高特异性的适体，对基体，神经毒性A的组件，并将这些适体作为用于AD诊断和治疗的新型，基于机制的工具。