West Lab Research

West Lab Research Focuses

Complex diseases require multi-disciplinary approaches for rationally based exploration of therapeutic discovery. The West laboratory is highly collaborative in nature, working side by side with medicinal chemists, geneticists, structural biologists, statisticians, bioinformatics specialists, proteomics and genomics experts, and clinicians, to fully pursue leads that might result in the discovery of efficacious therapies for neurological conditions like Parkinson’s disease and autism. 

Summaries of our current research projects are indicated below:
 

Characterization of biochemical pathways underlying late-onset Parkinson’s disease

Several pathogenic mutations that can cause late-onset PD localize to the leucine-rich repeat kinase 2 gene. Our ongoing studies have several goals: 1) to determine the enzymatic changes in the LRRK2 protein caused by the pathogenic mutations, particularly on LRRK2 kinase activity 2) To characterize the pathways that link together pathogenic LRRK2 with alpha-synuclein accumulation, and 3) To utilize LRRK2 as a foundation for the development of more relevant animal models of late-onset PD that should help in the development of disease-modifying therapeutics.

Neuron-MAP2

Pictured above are neurons stained with MAP2 (green color) expressing the LRRK2 protein kinase that are developing alpha-synuclein related pathology (pS129, red color).

Identification and characterization of clinical LRRK2 kinase inhibitors

Data from the West laboratory and other research groups indicate that LRRK2 kinase activity may be elevated in Parkinson’s disease, and that therapeutic down regulation of LRRK2 kinase activity may have neuroprotective benefit to individuals with late-onset Parkinson’s disease. The hypothesis is that administration of a LRRK2 inhibitor may slow or stop disease progression, and ameliorate additional symptoms of the disease through down-regulation of inflammation in the brain.  In 2009, the West laboratory entered into partnership with the Alabama Drug Discovery Alliance to find the best LRRK2 inhibitors that the desired profiles of potency, selectivity, and drug properties. The partnership is actively pursuing and optimizing lead compound series with the expectation that we will bring these the best drug to phase clinical trials in the coming years.


LRRK2-screen
Pictured above is a novel high-throughput screen for LRRK2 kinase inhibitors where hundreds of thousands of compound scaffolds were tested, and the best drugs are found and advanced to the next stage of development.

 

Developing new biomarkers for Parkinson’s disease and LRRK2 inhibitors

The West laboratory, together with 8 leading groups across the country, formed the initial working group of the collaborative for Parkinson’s disease biomarkers. https://pdbp.ninds.nih.gov/jsp/projects.jsp

With our collaborators at Johns Hopkins, Columbia, Mt. Sinai, Harvard, and Emory, we have initiated a major endeavor to find biomarkers for the diagnosis of Parkinson’s disease, uncover new pathways underlying disease susceptibility, and detect ways to track the LRRK2 kinase in PD affected individuals.

Parkinson-biomarkers 

See http://www.nih.gov/news/health/jan2013/ninds-15.htm for more information about the larger effort.