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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES024812&format=word)
| Principal Investigator: Mukhopadhyay, Somshuvra | |
|---|---|
| Institute Receiving Award | University Of Texas At Austin |
| Location | Austin, TX |
| Grant Number | R01ES024812 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Jan 2016 to 31 May 2028 |
| DESCRIPTION (provided by applicant): | ABSTRACT The essential metal manganese (Mn) accumulates in the basal ganglia at elevated levels and induces motor disease. Mn-induced motor disease is historically associated with occupational Mn exposure in adults. However, environmental exposure to elevated Mn has emerged as a more recent public health problem in infants, children and adolescents. Environmental Mn exposure in early-life substantially impairs motor function. But, the biology of Mn-induced motor disease in early-life is poorly understood, and there are no treatments for this condition. The fundamental question of how early-life, environmental Mn exposure impacts dopaminergic (DAergic) or GABAergic neurons in the basal ganglia that control movement to induce motor deficits is unanswered. This major knowledge gap exists because prior mechanistic work focused on the effects of Mn in adults. But, results from adults cannot be directly applied to early-life periods because environmental exposures are vastly different from occupational, early-life stages are more sensitive to Mn, and the impact of occupational Mn exposure on basal ganglia neurons is itself controversial. Our goal is to establish the effects of early-life, environmental Mn exposure on basal ganglia DAergic and GABAergic neurons that lead to motor disease. We will use innovative mouse models developed in the previous cycle that provide the feasibility, for the first time, to alter Mn levels specifically in DAergic or GABAergic neurons and isolate the role of the targeted neurons in Mn-induced motor disease. Our models are based on the neuron-specific knockout or knockin of the critical Mn efflux transporter SLC30A10. Pan-neuronal Slc30a10 knockouts had increased basal ganglia Mn levels and exhibited early-life motor deficits. Notably, Mn levels were elevated in targeted neurons of DAergic-specific or GABAergic-specific Slc30a10 knockouts, but only the DAergic-specific knockouts phenocopied the pan-neuronal strain and developed early-life motor deficits. These novel results lead to the hypothesis that Mn induces motor disease in early-life by targeting DAergic neurons. We will test our hypothesis through three specific aims. In Aim 1, we will use neuron-specific Slc30a10 knockout mice and test whether increasing Mn levels in DAergic, but not GABAergic, neurons enhances sensitivity to Mn-induced motor deficits. In Aim 2, we will use neuron-specific Slc30a10 knockin mice and test whether reducing Mn levels in DAergic, but not GABAergic, neurons protects against Mn neurotoxicity. We will use a combination of behavioral, microscopy, and neurochemical assays to distinguish between dysfunction or degeneration of DAergic or GABAergic neurons as the cause of early-life Mn-induced motor disease. In Aim 3, we will use a pharmacological approach and test whether dopamine agonists rescue early-life Mn-induced motor deficits. In totality, our studies (1) will establish a definitive neuronal mechanism of motor disease induced by environmental Mn exposure in early-life; and (2) may identify dopamine agonists to be a potential treatment for pediatric Mn-induced motor disease. |
| Science Code(s)/Area of Science(s) |
Primary: 63 - Neurodegenerative Secondary: - |
| Publications | See publications associated with this Grant. |
| Program Officer | Jonathan Hollander |