Behavioral characterization of humanized mouse model of eating disorder

饮食失调人源化小鼠模型的行为特征

基本信息

批准号：
9088580
负责人：
Huxing Cui
金额：
$ 22.84万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-05 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088580
关键词：
Affect Affective Alleles Animal Disease Models Animal Model Anorexia Anorexia Nervosa Anxiety Anxiety Disorders Behavior Behavioral Biological Body Image Body Weight Body Weight decreased Brain Breeding Bulimia Clinical Management Cognitive Consumption Dependovirus Dimensions Disease Distress Eating Eating Behavior Eating Disorders Environmental Risk Factor Face Family Female Female Adolescents Food Future Genes Genetic Genetic Risk Genetic Screening Genetic study Goals Grooming HDAC4 gene Heterozygote High Fat Diet Histone Deacetylase Homeostasis Human Human Genetics In Vitro Investigation Knock-in Knock-in Mouse Knowledge Link Medial Mediating Mental Depression Mental disorders Missense Mutation Modeling Molecular Mus Mutation National Institute of Mental Health Neuraxis Neurobiology Neurologic Neurons Pathway interactions Patients Pattern Phenotype Point Mutation Prefrontal Cortex Prevalence Process Proteins Psyche structure Regulation Repression Research Research Domain Criteria Research Proposals Risk Role Shapes Site Substance abuse problem Therapeutic Intervention Time Variant Weight Weight Gain Wild Type Mouse Work base brain circuitry emotional behavior estrogen-related receptor gain of function genetic variant humanized mouse improved in vivo innovation insight knockout gene male mortality mouse model neurotransmission novel overexpression preference public health relevance pup synaptic function theories transmission process treatment strategy trend

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由适用提供）：厌食症的神经和贪食症是严重的，令人衰弱的饮食失调形式（EDS），其特征是饮食行为以及对身体形状或体重的过度担忧。尽管EDS在任何精神疾病中具有最高的死亡率，并且经常与焦虑症和抑郁症共处，但由于缺乏可靠的动物模型，EDS的基本神经生物学基础仍然很少了解EDS的神经生物学基础。通过在受EDS严重影响的大型家庭中进行的全面遗传筛查，我们最近在组蛋白脱乙酰基酶4（HDAC4）基因中发现了有害的稀有错义突变（A786T），在HDAC4蛋白和与EDS共凝聚的HDAC4蛋白质中引起了功能。为了准确检查这种人遗传变异在开发ED中的作用，我们通过将人突变引入小鼠HDAC4基因来产生靶向敲入（Ki）小鼠系，以在小鼠HDAC4蛋白（A778T）的相应位点产生点突变。这项拟议的研究的基本原理是，这种独特的人性化小鼠的全面表征将证实该模型研究与饮食失调相关的行为的面部有效性，这将有助于识别一种新型的生物学途径将来针对治疗性干预。中心假设是HDAC4-A778T KI小鼠模仿人类遗传的EDS遗传风险将显示与EDS相关的某些行为表型。为此，已经产生了以下特定目标：1）确定小鼠中的HDAC4-A778T突变是否影响与ED相关的食物相关行为任务； 2）确定小鼠中的HDAC4-A778T突变是否影响与ED相关的强迫性和情绪行为。拟议的研究具有创新性，因为它首次将NIMH最近开发的研究领域标准（RDOC）矩阵与一种新型的ED型人工动物模型相结合，以确认面部有效性。拟议的研究也很重要，因为在这项研究建议中要进行的工作是研究神经生物学的连续研究的关键第一步。鉴于HDAC4与ED之间建立的遗传联系，预计所研究的行为维度将增强我们的理解并为这些疾病提供更好的治疗方法。