# Administrative Core

> **NIH NIH U54** · XAVIER UNIVERSITY OF LOUISIANA · 2020 · $348,650

## Abstract

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.

## Key facts

- **NIH application ID:** 10205647
- **Project number:** 3U54MD007595-12S2
- **Recipient organization:** XAVIER UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Guangdi Wang
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,650
- **Award type:** 3
- **Project period:** 2009-09-24 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205647

## Citation

> US National Institutes of Health, RePORTER application 10205647, Administrative Core (3U54MD007595-12S2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10205647. Licensed CC0.

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