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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(由申请人提供)：神经性厌食症和神经性暴食症是严重的、使人衰弱的饮食失调(EDS)形式，其特征是进食行为严重障碍，以及对身体形状或体重的痛苦或过度担忧。虽然抑郁症的死亡率是所有精神疾病中最高的，并且经常与焦虑症和抑郁症并存，但人们对抑郁症的潜在神经生物学基础仍然知之甚少。我们的长期目标是了解EDS的分子和神经基础，并利用这些知识开发更好的治疗策略。由于缺乏可靠的动物模型，对EDS的神经生物学基础的了解一直受到限制。通过在严重受EDS影响的大型家庭中进行全面的基因筛查，我们最近发现了组蛋白脱乙酰基酶4(HDAC4)基因的一个有害的罕见错义突变(A786T)，该突变导致HDAC4蛋白的功能获得，并与EDS共分离。为了准确地研究这种人类基因变异在ED发生中的作用，我们有一个靶向敲入(KI)小鼠系，方法是将人类突变引入小鼠HDAC4基因，在小鼠HDAC4蛋白(A778T)的相应位置产生点突变。这项拟议研究的基本原理是，对这只独特的人源化小鼠的综合特征将证实该模型在研究进食障碍相关行为方面的表面有效性，这将有助于识别一种新的生物学途径，这可能是未来的目标是进行治疗干预。中心假设是，模拟人类遗传风险的HDAC4-A778T Ki小鼠将表现出与EDS相关的一些行为表型。为此，已经产生了以下具体目标：1)确定小鼠的HDAC4-A778T突变是否影响与EDS相关的食物相关行为任务；以及2)确定小鼠的HDAC4-A778T突变是否影响与EDS相关的强迫感和情绪行为。这项拟议的研究具有创新性，因为它将首次将NIMH最近开发的研究领域标准(RDoC)矩阵与一种新的EDS人性化动物模型相结合，以确认其表面有效性。这项拟议的研究也具有重要意义，因为这项研究计划中将要开展的工作是在分子、细胞和大脑电路水平上研究ED的神经生物学基础的连续研究的关键的第一步。鉴于HDAC4和EDS之间已建立的遗传联系，正在研究的行为维度有望增进我们的理解，并为这些疾病提供更好的治疗方法。