Administrative Core

阿尔茨海默病(AD)在非裔美国人(AA)人口中的高患病率 被阿尔茨海默氏症协会确定为一种新兴的健康危机。趁有机会 与非白人相比，患有AD的非裔美国人的比例已经不成比例了 拉美裔人口(占全国所有AD病例的20%)，这一比例预计将增加 到2050年，全国所有病例的42%。因此，迫切需要解决这一问题 当前的和不断扩大的健康差距。AD的主要特征之一是紧张症，即 脑组织中的神经原纤维缠结(NFTs)。NFTs是tau的聚集体，tau是一种蛋白质， 正常情况下结合并稳定神经元中的微管网络。从陶的过渡 导致NFTs的微管与非结合形式的生理联系是由于 一系列细胞激酶对tau蛋白的过度磷酸化。不光是陶 过度磷酸化导致NFTs的形成，但其与微管的解离导致 它们的不稳定，从而对神经元的运输和组织产生影响。 因此，防止tau过度磷酸化是开发新的 治疗阿尔茨海默病。我们的项目以抑制酪蛋白激酶1δ/ε为目标，已知 在参与微管结合的残基上磷酸化tau蛋白。我们的实验室有 确定了两类抑制酪蛋白激酶1δ/ε，阻断tau磷酸化的分子 在基于细胞的分析中。这项提议的目标是优化这些先导化合物，使其具有潜在的 药效增强的治疗学。将使用计算分子建模工具来 设计将使用有机合成方法合成的新衍生品。要确定 这些新化合物在抑制CK1δ/ε方面的有效性，我们将在 使用纯化组分的tau磷酸化重组生化分析。结束 这些检测的产物也将接受微管亲和分析，以表明 抑制Tau的CK1依赖的磷酸化维持其生理相关的作用 Tau，阻断NFTs的病理发展。这些化合物是通过这种方式发展起来的 经过进一步的临床前和临床试验，PROCESS可作为治疗AD的潜在药物。 该项目将利用已建立的现有RCMI基础设施 路易斯安那州泽维尔大学，全国首屈一指的STEM教育和 研究。

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.