Neuroinflammation manipulation in ALS via Drosophila models of TBK1 mutations

Overview

This research program addresses amyotrophic lateral sclerosis (ALS) by targeting TBK1, a neuroinflammatory kinase linked to disease pathogenesis. Multiple TBK1 mutations have been associated with ALS, and this project investigates whether modulating the activity of these mutant variants can serve as a pharmaceutical strategy for disease intervention. The work combines computational mutation analysis with Drosophila genetic models to identify lead compounds capable of influencing TBK1-associated neuroinflammation pathways.

Technical specifications

Research approach:

• Compilation of a comprehensive database of TBK1 mutations reported in ALS patients
• Preliminary protein sequence and structural analysis categorizing mutants into functional impairment groups
• Established Drosophila ALS models with engineered IK2 mutant genes corresponding to human ALS-associated TBK1 mutations
• Computational screening of chemical databases for compounds that modulate mutant TBK1 and IK2
• Machine learning classification of gene expression profiles to rank candidate compounds
• Experimental validation of top-ranked candidates in Drosophila ALS models
• Identification of lead compounds for potential pharmaceutical development targeting TBK1-associated inflammation pathways

Collaborative structure:

• Led by Dr. Fang He at Texas A&M University-Kingsville and Dr. Dapeng Zhang at Saint Louis University
• Combines expertise in computational biology, Drosophila genetics, and neuroinflammation research

Technology readiness level

The project is at an early-to-mid stage of preclinical research. The research team has completed preliminary computational analysis of TBK1 mutations and developed the necessary Drosophila genetic constructs. Future validation efforts will focus on systematic computational analysis of patient mutations, chemical screening, and experimental validation in fly models. The goal is to identify lead compounds suitable for further pharmaceutical development in animal models and eventual translation to ALS patients.