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Functional mapping of arginine vasopressin receptor 1A circuits that promote anorexic behavior

促进厌食行为的精氨酸加压素受体 1A 电路的功能图谱

基本信息

批准号：
10321547
负责人：
Lori M Zeltser
金额：
$ 46.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321547
关键词：
Adolescence Adolescent Alleles Amygdaloid structure Anorexia Anorexia Nervosa Argipressin Behavior Biological Body Weight decreased Brain Brain region Brain-Derived Neurotrophic Factor Caloric Restriction Cell Nucleus Cessation of life Cholera Toxin Protomer B Collaborations Cre driver Development Diagnosis Disease Eating Eating Behavior Epidemiology Exhibits Exposure to Fasting Feeding behaviors Female Foundations Future Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic study Goals Human Injections Knock-out Lead Life Malnutrition Maps Medical Mental disorders Methods Microinjections Modeling Mood Disorders Mouse Strains Mus Neurobiology Neurons Neurosecretory Systems Onset of illness Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacology Phase II Clinical Trials Physiological Population Predisposition Prevalence Risk Risk Factors Severities Signal Transduction Site Social isolation Source Stains Stress Symptoms Techniques Time V1a vasopressin receptor Variant Visualization Wild Type Mouse anorexic antagonist anxiety-related disorders arginine treatment base comorbidity design designer receptors exclusively activated by designer drugs dietary restriction effective therapy environmental stressor experimental study feeding gene environment interaction insight interest mortality mouse model nestin protein new therapeutic target phase II trial psychologic receptor social stress

项目摘要

PROJECT SUMMARY Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, and there are no effective treatments. A major obstacle to identifying new therapeutic targets is the lack of insight into causes of the pathophysiological eating behavior. Malnutrition and co-morbid psychiatric illnesses cause dramatic changes in the brain and periphery that complicate efforts to uncover factors responsible for disease onset. The Zeltser lab developed a new mouse model to study AN at the stage of illness prior to disease conversion by taking advantage of an epidemiological observation that is often overlooked – genetic susceptibility in adolescence. Female mice carrying an allele associated with genetic susceptibility to AN (BDNF-Val66Met) were exposed to social isolation stress and caloric restriction during adolescence. Approximately 40% of these mice exhibit severe self-imposed dietary restriction, sometimes to the point of death. Studies using this mouse model of the pre-AN state identified a novel therapeutic target for AN treatment: arginine vasopressin receptor 1A (AVPR1A). The proposed experiments will map the AVP→ AVPR1A circuits in the brain that are necessary and sufficient to suppress feeding and will determine which are potentiated by gene x environment interactions that promote susceptibility to anorexic behavior. Studies outlined in Aim 1 will utilize pharmacological, genetic and pharmacogenetic approaches to define populations of AVPR1A neurons that are necessary and sufficient to suppress feeding in wild-type mice. In parallel, experiments in Aim 2 will use a combination of retrograde tracing and pharmacogenetic techniques to identify neuronal populations that transmit the anorexic AVP signal. Since there are many distinct circuits that regulate feeding, studies in Aim 3 will determine where anorexic effects of AVP and the expression of AVPR1A pathway components are enhanced in hBDNFMet/? females exposed to peri-pubertal social isolation stress. The elucidation of brain circuits that promote anorexic behavior in our mouse model would provide a strong foundation for future efforts to explore whether AVPR1A antagonists that are currently in Phase II clinical trials for other psychiatric indications could benefit some AN patients. Lessons learned will also significantly advance the understanding of how the common BDNF-Val66Met variant exacerbates the effects of social stress on the adolescent brain to increase susceptibility to a variety of anxiety-related and affective disorders.

项目摘要神经性厌食症（AN）在所有精神疾病中死亡率最高，有效的治疗。识别新治疗靶点的一个主要障碍是缺乏洞察力病理生理性进食行为的原因营养不良和合并精神病疾病会导致大脑和周边发生巨大变化，导致疾病发作的因素。Zeltser实验室开发了一种新的小鼠模型来研究AN 在疾病转化之前的疾病阶段，经常被忽视的观察-青春期的遗传易感性。雌性小鼠携带与AN遗传易感性相关的等位基因（BDNF-Val 66 Met）暴露于社会隔离压力和热量限制。大约40%的老鼠表现出严重的自我强加的饮食限制，有时甚至到了死亡的地步。研究使用此前AN状态的小鼠模型确定了AN治疗的新治疗靶点：精氨酸加压素受体1A（AVPR 1A）。拟议的实验将绘制大脑中AVP→ AVPR 1A回路，并足以抑制进食，并将确定哪些是由基因x环境增强的相互作用，促进易感性的行为。目标1中概述的研究将利用药理学、遗传学和药物遗传学方法来定义AVPR 1A群体这些神经元是抑制野生型小鼠进食所必需和足够的。与此同时，目标2中的实验将结合使用逆行追踪和药物遗传学技术，以确定神经元群体，传输精氨酸加压素信号。既然有许多不同的回路调节进食，目标3中的研究将确定在哪些地方， AVP和AVPR 1A通路组分的表达在hBDNFMet/？女性暴露在青春期社会隔离压力下在我们的小鼠模型中，对促进神经行为的脑回路的阐明将提供为未来探索AVPR 1A拮抗剂是否是目前在其他精神适应症的II期临床试验可能使一些AN患者受益。教训这一发现也将大大促进人们对常见的BDNF-Val 66 Met 变异加剧了社会压力对青少年大脑的影响，增加了易感性各种焦虑相关的情感障碍

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rethinking the Approach to Preclinical Models of Anorexia Nervosa.

DOI：
10.1007/s11920-022-01319-2
发表时间：
2022-01
期刊：
Current psychiatry reports
影响因子：
6.7
作者：
François M;Zeltser LM
通讯作者：
Zeltser LM

Corrigendum: MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

勘误表：骨源性脂质运载蛋白 2 对 MC4R 依赖性食欲的抑制。

DOI：
10.1038/nature22808
发表时间：
2017
期刊：
Nature
影响因子：
64.8
作者：
Mosialou,Ioanna;Shikhel,Steven;Liu,Jian-Min;Maurizi,Antonio;Luo,Na;He,Zhenyan;Huang,Yiru;Zong,Haihong;Friedman,RichardA;Barasch,Jonathan;Lanzano,Patricia;Deng,Liyong;Leibel,RudolphL;Rubin,Mishaela;Nickolas,Thomas;Chung,Wen
通讯作者：
Chung,Wen

A Framework for Developing Translationally Relevant Animal Models of Stress-Induced Changes in Eating Behavior.