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Mouse Models Containing Human Alleles: Novel Tools to Study Brain Function

NAMHC Concept Clearance

Presenter

Andrea Beckel-Mitchener, Ph.D.
Program Chief, Functional Neurogenomics Program
Molecular, Cellular and Functional Genomic Neuroscience Research Branch
Division of Neuroscience and Basic Behavioral Science

Goal

This initiative will support the development and characterization of novel mouse models that express human genes or human genetic elements that can aid in understanding the molecular mechanisms underlying brain function relevant to the research priorities of NIMH.

Rationale

In recent years, through genome association studies and other means, a number of genes have emerged as candidates for involvement in human mental disorders. Although unclear at the moment, some of these may be specific "disease alleles" with polymorphisms present either in the coding region or in regulatory elements altering the function or expression characteristics of that particular gene. Other genes may, in isolation or in combination, be "protective" for unknown functional reasons. In addition, there are indications that "gene dosage" might play a role in various human pathologies of interest to NIMH. At present, little is known about the mechanisms or pathways that contribute to functional changes for these human genes or the consequences of these changes on brain function or behavior.

One approach to studying candidate genes and their function is the use of genetically-altered experimental mice. Expressing specific human alleles of interest can increase our understanding of processes related to gene/protein regulation and function in brain development, physiology, pharmacology, neurochemistry, and behavior. The approach would provide a novel physiological context in which to ask basic functional questions about human genes and proteins and has already been used with some success, including in the context of neurological conditions. This effort is consistent with the ongoing commitment by NIMH towards promoting the development of novel tools that can be used to evaluate genes implicated in mental disorders as well as human genes involved in basic brain function.

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