A5076962361- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Genomics and Rare Diseases
- Ion channel regulation and function
- Genetic Associations and Epidemiology
- Protein Kinase Regulation and GTPase Signaling
- Protein Tyrosine Phosphatases
- Ubiquitin and proteasome pathways
- Molecular Sensors and Ion Detection
- Galectins and Cancer Biology
- Photochromic and Fluorescence Chemistry
- Chronic Disease Management Strategies
- Pharmacological Receptor Mechanisms and Effects
- Phosphodiesterase function and regulation
- Monoclonal and Polyclonal Antibodies Research
- BRCA gene mutations in cancer
Vanderbilt University Medical Center
2006-2018
Vanderbilt University
2008-2010
VA Tennessee Valley Healthcare System
2010
United States Department of Veterans Affairs
2010
To compare three groupings of Electronic Health Record (EHR) billing codes for their ability to represent clinically meaningful phenotypes and replicate known genetic associations. The tested coding systems were the International Classification Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, Agency Healthcare Research Quality Software ICD-9-CM (CCS), manually curated "phecodes" designed facilitate phenome-wide association studies (PheWAS) in EHRs.We selected 100 disease...
Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach aggregates on the basis of patterns described by Mendelian diseases. mapped clinical 1204 diseases into captured from electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In initial validation, PheRS distinguished cases controls five Applying to 21,701 genotyped individuals...
Parkinson's disease (PD) is caused by the death of dopamine neurons in basal ganglia and results motor symptoms such as tremor bradykinesia. Activation metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission antiparkinsonian effects rodent PD models. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) a positive allosteric modulator (PAM) mGluR4 that used further validate role PD, but compound suffers from lack selectivity, relatively low...
Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles mGluR5 potential usefulness treatment these there are limitations in tools available, poor selectivity, low potency, limited solubility. To address issues, we an innovative assay that allows simultaneous screening agonists,...
Activators of M<sub>1</sub> muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer9s disease. Unfortunately, the development M<sub>1</sub>-active compounds has resulted in nonselective activation highly related M<sub>2</sub> to M<sub>5</sub> mAChR subtypes, which results dose-limiting side effects. Using a functional screening approach, we identified several ligands that potentiated agonist with low micromolar potencies induced 5-fold or...
This report describes the discovery and initial characterization of first positive allosteric modulator muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation at M1, M3, M5 receptors in cell-based Ca2+ mobilization assays. Subsequent optimization led to VU0238429, possessed an EC50 approximately 1.16 μM with >30-fold selectivity versus M1 no M2 M4 potentiator activity.
Abstract PTP69D is a receptor protein tyrosine phosphatase that was identified as key regulator of neuromuscular axon guidance in Drosophila , and has subsequently been shown to play similar role the central nervous system retina. Three Ptp69D alleles with mutations involving catalytically important residues exhibit high degree phenotypic variation viability mutant adult flies ranging from 0 96%, ISNb motor nerve defects 11 57% [Desai Purdy, 2003 ]. To determine whether affecting demonstrate...
Activation of muscarinic acetylcholine receptor subtype-1 (M1) has been investigated preclinically as a potential strategy for treatment Alzheimer's disease (AD). Selective targeting subtype-5 (M5) may also be therapeutically relevant to AD due its role in regulation cerebral vascular tone and certain cognitive functions suggested by studies with M5-KO mice. Historically, high homology the orthosteric acetylcholine-binding site across five subtypes made discovery development highly...