Huntington Disease (HD) is a neurodegenerative disorder pathologically characterized by selective degeneration of neurons within the striatum, cortex and hypothalamus. HD is caused by a CAG repeat expansion within the HTT gene, with longer repeats being strongly associated with earlier age-of-onset. Although repeat length explains over half of the variability in age of onset, a landmark genetic study attributed the majority of residual variability to unknown environmental factors. Metal ions with neurotoxic properties are strong candidates for environmental agents that may modulate selective neurodegenerative process like HD because, (1) the differential accumulation of various metals across neuronal subtypes, (2) the similarities between metal ion cytotoxicity and cellular pathways of neurodegeneration, and (3) our research in the previous funding cycle demonstrating altered vulnerability in mouse models of HD to both manganese and cadmium. The long-term goal of this research program is to reveal the pathogenic mechanisms underlying gene-environment interactions in neurodegenerative disease, focusing on HD given its clearly defined genetic etiology, to inform environmental health strategies to delay disease onset or slow the progression of disease. Our highly innovative approach combines (a) a novel high-throughput method to quantify cellular Mn status, (b) a state-of-the-art high throughput screen (HTS) facility at the Vanderbilt Institute of Chemical Biology (VICB), and (c) the clinical relevance of a patient-specific neuronal model system based on human induced pluripotent stem cell (hiPSC) technology.
Aim 1 will test the hypothesis that an HD striatal Mn handling deficit discovered in the previous funding cycle will enable a HTS to find small molecules that mitigate the actions of HD environmental risk factors.
Aim 2 will test the hypothesis that human striatal neuroprogenitors (NPs) from HD patients have increased sensitivity to non-cytotoxic levels of metal toxicants impinging upon specific stress response pathways.
Aim 3 will test the clinical potential of small molecule modifiers of environmental risk factors in HD and whether the magnitude of HD-specific toxicant vulnerability will correlate by patient with established disease-modifiers such as neural lineage specificity, CAG-repeat length and clinical variation in age-of-onset.
These specific aims will reveal disease-relevant environmental stress responses and identify small molecules to mitigate vulnerabilities and restore neuronal homeostasis in HD. Furthermore, discovery of toxicant interactions and patient-specific responses may inform environmental health strategies to delay disease onset or slow the progression of HD using a personalized medicine approach.

Public Health Relevance

The proposed studies will (1) evaluate p53 and AKT/mTOR cell stress signaling pathways as mediators of gene-environment interactions in Huntington disease (HD), (2) test whether human striatal neuroprogenitors derived from HD patients will exhibit selective vulnerability to Mn and other neurotoxicants that impinge upon these specific stress response pathways, (3) validate the pathogenic relevance of these pathways in an in vivo HD mouse model, and (4) determine if patient variation in HD age-of-onset correlates with sensitivity to HD- relevant neurotoxicants. Our multidisciplinary approach seeks to define the functional domains that underlie modulation of HD by environmental risk factors and identify the clinical correlates of the stress response pathways that underlie this neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES016931-06A1
Application #
8695026
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Hollander, Jonathan
Project Start
2008-08-15
Project End
2019-02-28
Budget Start
2014-05-07
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$352,569
Indirect Cost
$127,569
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Feaster, Tromondae K; Cadar, Adrian G; Wang, Lili et al. (2015) Matrigel Mattress: A Method for the Generation of Single Contracting Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circ Res 117:995-1000
Kumar, Kevin K; Goodwin, Cody R; Uhouse, Michael A et al. (2015) Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status. Metallomics 7:363-70
Chun, Young Wook; Balikov, Daniel A; Feaster, Tromondae K et al. (2015) Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes. Biomaterials 67:52-64
Horning, Kyle J; Caito, Samuel W; Tipps, K Grace et al. (2015) Manganese Is Essential for Neuronal Health. Annu Rev Nutr 35:71-108
Aboud, Asad A; Tidball, Andrew M; Kumar, Kevin K et al. (2015) PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper. Neurobiol Dis 73:204-12

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