Administrative Core

行政核心

• 批准号: 10205647
• 负责人: Guangdi Wang
• 金额: $ 34.87万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205647
• 关键词: Address; Affect; Affinity; African American; Alzheimer' s Disease; Alzheimer' s disease therapeutic; Axon; Axonal Transport; Binding; Binding Proteins; Biochemical; Biological Assay; Biomedical Research; Blood - brain barrier anatomy; Brain; CSNK1A1 gene; Cells; Cellular Assay; Charge; Clinical; Communities; Computer Models; Databases; Development; Disease; Dissociation; Docking; Elderly; Epidemic; Evaluation; Fluorescence Resonance Energy Transfer; Generations; Genes; Goals; Health; High Prevalence; Hispanics; Historically Black Colleges and Universities; Human; In Vitro; Infrastructure; Institution; Isoelectric Point; Laboratories; Lead; Lesion; Louisiana; Methods; Microtubule Depolymerization; Microtubule Stabilization; Microtubules; Molecular Computations; Neurofibrillary Tangles; Neurons; Pathologic; Phosphorylation; Phosphotransferases; Physiological; Population; Preclinical Testing; Process; Protein Isoforms; Proteins; Public Health; Recombinants; Research; Role; Science, Technology, Engineering and Mathematics Education; Series; Site; Surface; Tauopathies; Testing; Therapeutic; United States; Universities; base; brain tissue; casein kinase; casein kinase I; design; education research; effective therapy; health disparity; improved; in silico; inhibitor/antagonist; investigator training; lead optimization; minority undergraduate; molecular modeling; neurofibrillary tangle formation; neuronal transport; novel; novel therapeutics; overexpression; preclinical evaluation; prevent; programs; reconstitution; research clinical testing; small molecule; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutic development; therapeutic target; tool; undergraduate student

The high prevalence of Alzheimer’s disease (AD) in the African American (AA) population has been identified as an emerging health crisis by the Alzheimer’s Association. While there is already a disproportionate percentage of African Americans with AD relative to the non-white Hispanic population (20% of all AD cases nationwide), this percentage is expected to increase to 42% of all cases nationwide by 2050. As such, there is an urgent need to address this current and growing health disparity. One of the key hallmarks of AD is tauopathy, the presence of neurofibrillary tangles (NFTs) in brain tissue. NFTs are aggregates of tau, a protein that normally binds to and stabilizes the microtubule network in neurons. The transition from tau’s physiological association with the microtubule to the unbound form that leads to NFTs is due to the hyperphosphorylation of tau by a number of cellular kinases. Not only does tau hyperphosphorylation lead to the formation of NFTs, but its dissociation from microtubules leads to their destabilization, with resulting impacts on neuronal transport and organization. Preventing hyperphosphorylation of tau is thus a key target for the development of novel therapeutics for AD. Our project targets the inhibition of casein kinase 1 δ/ε that are known to phosphorylate the tau protein at residues involved in microtubule binding. Our laboratory has identified two classes of molecules that inhibit casein kinase 1δ/ε, blocking tau phosphorylation in cell-based assays. The goal of this proposal is to optimize these lead compounds to potential therapeutics with increased potency. Computational molecular modeling tools will be used to design new derivatives that will be synthesized using organic synthetic methods. To determine the efficacy of these new compounds in the inhibition of CK1δ/ε, we will test them in a reconstituted biochemical assay of tau phosphorylation using purified components. The end products of these assays will also be subjected to microtubule affinity assays to show that inhibiting CK1-dependent phosphorylation of tau maintains the physiologically relevant role of tau and blocks the pathological development of NFTs. The compounds developed through this process can serve as potential therapeutics for AD after further pre-clinical and clinical testing. This project will capitalize on the existing RCMI infrastructure that has been established at Xavier University of Louisiana, one of the nation’s premier HBCUs for STEM education and research.

非裔美国人（AA）人群中阿尔茨海默病（AD）的高患病率， 被阿尔茨海默氏症协会认定为一种新出现的健康危机。虽然 与非白人相比，患有AD的非裔美国人的比例已经不成比例， 西班牙裔人口（占全国所有AD病例的20%），这一比例预计将增加 到2050年将占全国病例的42%。因此，迫切需要解决这一问题 目前和日益增长的健康差距。AD的关键特征之一是tau蛋白病， 脑组织中的神经纤维缠结（NFT）。NFT是tau的聚集体，tau是一种蛋白质， 通常与神经元中的微管网络结合并使其稳定。从tau的转变 与微管的生理关联导致NFT的未结合形式是由于 tau蛋白被许多细胞激酶过度磷酸化。不仅陶 过度磷酸化导致NFT的形成，但其从微管中解离导致 它们的不稳定性，从而对神经元的运输和组织产生影响。 因此，防止tau蛋白的过度磷酸化是开发新的免疫抑制剂的关键靶标。 AD的治疗方法。我们的项目的目标是抑制酪蛋白激酶1 δ/ε，这是已知的， 在涉及微管结合的残基处磷酸化tau蛋白。本实验室 鉴定了两类抑制酪蛋白激酶1δ/ε的分子，阻断tau蛋白磷酸化 在基于细胞的分析中。该提案的目标是优化这些先导化合物， 具有增加的效力的治疗剂。计算分子建模工具将用于 设计新的衍生物，将使用有机合成方法合成。以确定 这些新化合物在抑制CK 1 δ/ε中的功效，我们将在一个实验室中测试它们。 使用纯化的组分进行tau磷酸化的重构生物化学测定。年底 这些测定的产物也将进行微管亲和性测定， 抑制tau蛋白的CK 1依赖性磷酸化， tau蛋白，并阻断NFT的病理发展。通过这种方法产生的化合物 在进一步的临床前和临床试验后，该方法可以作为AD的潜在治疗剂。 该项目将利用现有的RCMI基础设施， 路易斯安那州泽维尔大学是全国首屈一指的STEM教育HBCU之一， research.