NOVEL BIFUNCTIONAL CHEMICAL AGENTS AS THERANOSTIC TOOLS FOR AMYLOID DISEASES

新型双功能化学制剂作为淀粉样蛋白疾病的治疗工具

• 批准号: 9277494
• 负责人: LIVIU M. MIRICA
• 金额: $ 28.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277494
• 关键词: Affect; Affinity; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Attenuated; Autopsy; Binding; Brain; Chelating Agents; Chemical Agents; Copper; Data; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Exhibits; Goals; Health; Huntington Disease; Image; Investigation; Ions; Lead; Mass Spectrum Analysis; Mediating; Metals; Mission; Molecular; Neurodegenerative Disorders; Outcome; Parkinson Disease; Patients; Peptides; Play; Positron-Emission Tomography; Prevention; Prion Diseases; Property; Proteins; Public Health; Radioisotopes; Radiolabeled; Research; Research Project Grants; Role; Senile Plaques; Testing; Therapeutic Agents; Tracer; Transition Elements; United States National Institutes of Health; Work; abeta oligomer; abeta toxicity; amyloid imaging; base; disease diagnosis; imaging agent; insight; metal chelator; neurotoxic; neurotoxicity; novel; novel diagnostics; novel strategies; novel therapeutics; public health relevance; theranostics; tool

DESCRIPTION (provided by applicant): The aggregation of peptides and proteins plays a key role in many devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and the prion diseases. Although the insoluble amyloid fibrils have long been viewed as the hallmark of these diseases, the soluble oligomers formed by various amyloidogenic peptides have begun to be recognized as the more relevant neurotoxic species involved in these diseases. Among these amyloid disorders, Alzheimer's disease (AD) is the most common neurodegenerative disease. To date there is no treatment for AD and its diagnosis with high accuracy requires a detailed post-mortem examination of the brain. Thus, new insights provided by a detailed investigation at the molecular level of the role o different factors in AD may have a large health-related impact and may allow for the development of novel therapeutics and diagnostic tools for AD. The brains of AD patients are characterized by the deposition of amyloid plaques that contain the amyloid ß (Aß) peptide. In addition, it is known that metal ions can interact with the Aß peptide and dramatically affect its aggregation properties. The long-term goal of this research project is to develop novel therapeutic and diagnostic agents for various amyloid disorders, including Alzheimer's disease. The hypothesis is that transition metal ions, especially copper, increase the toxicity of Aß aggregates by stabilizing the soluble Aß oligomers. The rationale for the proposed research is that the development of bifunctional metal-binding and metal-containing compounds with high affinity for different amyloid aggregates - including soluble Aß oligomers, will result in a novel approach for the development of theranostic agents for AD and possibly other amyloid disorders. The first specific aim is to develop novel bifunctional metal-binding compounds that modulate the metal-mediated stabilization and neurotoxicity of soluble Aß oligomers. Based on our preliminary data, the working hypothesis here is that transition metal ions stabilize the soluble Aß oligomers, with direct implications into how metal ions enhance the neurotoxicity of Aß oligomers. The second specific aim is to develop 64Cu-radiolabeled compounds for positron emission tomography (PET) imaging of amyloid aggregates, including soluble Aß oligomers, as an early diagnostic tool for AD and other amyloid disorders.

描述(由申请人提供)：多肽和蛋白质的聚集在许多毁灭性的神经退行性疾病中起着关键作用，包括阿尔茨海默病、帕金森病、亨廷顿病和普里恩病。虽然不溶性淀粉样蛋白纤维长期以来一直被视为这些疾病的标志，但由各种淀粉样肽形成的可溶性寡聚体已经开始被认为是与这些疾病有关的更相关的神经毒性物种。在这些淀粉样变性疾病中，阿尔茨海默病(AD)是最常见的神经退行性疾病。到目前为止，阿尔茨海默病还没有治疗方法，其高准确率的诊断需要对大脑进行详细的尸检。因此，在分子水平上对不同因素在AD中的作用进行详细研究提供的新见解可能会对健康产生重大影响，并可能允许开发新的AD治疗和诊断工具。阿尔茨海默病患者大脑的特点是沉积了含有淀粉样多肽的淀粉样斑块。此外，已知金属离子可以与A？多肽相互作用并显著影响其聚集性质。该研究项目的长期目标是为包括阿尔茨海默病在内的各种淀粉样变性疾病开发新的治疗和诊断试剂。假设过渡金属离子，尤其是铜，通过稳定可溶的低聚物而增加了Aü聚集体的毒性。这项研究的基本原理是，开发对不同的淀粉样蛋白聚集体具有高亲和力的双功能金属结合和含金属化合物--包括可溶性A？低聚物，将为开发治疗AD和可能的其他淀粉样蛋白疾病的治疗药物提供一种新的方法。第一个具体目标是开发新型的双功能金属结合化合物，以调节可溶低聚物的金属介导的稳定性和神经毒性。根据我们的初步数据，这里的工作假设是过渡金属离子稳定了可溶的A？低聚物，这直接影响了金属离子如何增强A？低聚物的神经毒性。第二个具体目标是开发64铜放射性标记化合物，用于淀粉样聚集体的正电子发射断层扫描(PET)成像，包括可溶性低聚物，作为AD和其他淀粉样变性疾病的早期诊断工具。