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）：肽和蛋白质的聚集在许多破坏性神经退行性疾病中发挥着关键作用，包括阿尔茨海默病、帕金森病、亨廷顿病和朊病毒病，尽管不溶性淀粉样原纤维长期以来一直被视为疾病的根源。作为这些疾病的标志，由各种淀粉样肽形成的可溶性寡聚体已开始被认为是与这些疾病相关的更相关的神经毒性物质。淀粉样蛋白疾病，阿尔茨海默病（AD）是最常见的神经退行性疾病，迄今为止，AD 尚无治疗方法，其诊断需要对大脑进行详细的尸检，因此，详细的研究提供了新的见解。不同因素在 AD 中的作用的分子水平可能会产生与健康相关的巨大影响，并可能有助于开发新的 AD 治疗方法和诊断工具。 AD 患者的大脑的特点是含有淀粉样蛋白斑块的沉积。 β淀粉样蛋白此外，众所周知，金属离子可以与 Aß 肽相互作用并显着影响其聚集特性，该研究项目的长期目标是开发用于各种淀粉样蛋白疾病的新型治疗和诊断剂。阿尔茨海默病的假设是过渡金属离子，尤其是铜，通过稳定可溶性 Aß 低聚物来增加 Aß 聚集体的毒性。该研究的基本原理是双功能的开发。对不同淀粉样蛋白聚集体（包括可溶性 Aß 寡聚体）具有高亲和力的金属结合和含金属化合物，将为开发 AD 和可能的其他淀粉样蛋白疾病的治疗诊断药物提供新方法。第一个具体目标是开发新型双功能。调节可溶性 Aß 低聚物的金属介导的稳定性和神经毒性的金属结合化合物 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可溶性 Aß。第二个具体目标是开发用于淀粉样蛋白聚集体（包括可溶性 Aß 寡聚物）正电子发射断层扫描 (PET) 成像的 64Cu 放射性标记化合物，作为早期诊断工具。 AD 和其他淀粉样蛋白疾病。