Anorexia nervosa and bulimia nervosa are severe, debilitating forms of eating disorders (EDs) characterized by significant disturbances in eating behavior and by distress or excessive concern about body shape or weight. While EDs have the highest mortality rate of any mental illness and are frequently co-morbid with anxiety disorders and depression, the underlying neurobiological basis of EDs remain poorly understood. Our long-term goal is to understand the molecular and neuronal basis of EDs and to use this knowledge to develop better treatment strategies. Understanding the neurobiological basis of EDs has been limited due to lack of a reliable animal model of the disease. Through a comprehensive genetic screening in large families severely affected by EDs, we have recently discovered a deleterious rare missense mutation (A786T) in the histone deacetylase 4 (HDAC4) gene that causes a gain-of-function in the HDAC4 protein and co-segregate with EDs. In order to precisely examine the role of this human genetic variant in developing an ED, we had a targeted knock-in (KI) mouse line generated by introducing the human mutation into the mouse Hdac4 gene to generate a point mutation at the corresponding site of the mouse Hdac4 protein (A778T). The rationale for this proposed research is that comprehensive characterization of this unique humanized mouse will confirm the face validity of the model to study eating disorder-related behaviors, which will help to identify a novel biological pathway that could potentially be targeted in the future for a therapeutic intervention. The central hypothesis is that Hdac4-A778T KI mice mimicking the human genetic risk of developing EDs will display some behavioral phenotypes relevant to EDs. To this end, the following Specific Aims have been generated: 1) Determine if the HDAC4-A778T mutation in mice affects food-associated behavioral tasks relevant to EDs; and 2) Determine if the HDAC4-A778T mutation in mice affects compulsivity and emotional behaviors relevant to EDs. The proposed research is innovative as it will, for the first time, combine the Research Domain Criteria (RDoC) Matrix recently developed by the NIMH with a novel humanized animal model of EDs to confirm the face validity. The proposed research is also significant because the work to be carried out in this research proposal is the critical first step in a continuum of research investigating the neurobiological basis of EDs at th molecular, cellular and brain circuitry levels. Given the established genetic link between HDAC4 and EDs, the behavioral dimensions under investigation are expected to enhance our understanding and inform better treatments for these disorders.
Anorexia nervosa and bulimia nervosa are severe, debilitating eating disorders with the highest mortality rate of any mental illnesses. Unfortunately, current treatments are inadequate in part because the underlying basis of eating disorders remains poorly understood. This research proposal will examine a newly created mouse model of eating disorder behaviors based upon a mutation discovered in humans that increases the risk of developing an eating disorder to provide new insights into the neurological basis of eating disorders and to identify new opportunities for therapeutic intervention.
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