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Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

表观遗传对大脑中甲状腺激素作用和行为的影响

基本信息

批准号：
10294251
负责人：
Arturo Hernandez
金额：
$ 38.9万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-26 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294251
关键词：
Adult Affect Alleles Anxiety Attention deficit hyperactivity disorder Award Behavior Behavior Disorders Behavioral Bipolar Disorder Brain Brain region Candidate Disease Gene Circadian Rhythms Clinical Complex Data Development Developmental Gene Diagnosis Disease Elderly Endocrine Endogenous Factors Environmental Risk Factor Epidemiology Epigenetic Process Etiology Exposure to Family Female Functional disorder Gene Expression Gene Expression Profiling Generations Genes Genetic Genetic Code Genetic study Goals Healthcare Systems Heritability Hypothalamic structure Individual Inheritance Patterns Inherited Knowledge Lead Life Link Mental Depression Molecular Monitor Mothers Mus Nervous System Physiology Neuraxis Neurodevelopmental Disorder Neurologic Neurons Onset of illness Pathologic Pattern Peripheral Phenotype Physical activity Play Population Predisposition Pregnant Women Prevalence Prevention Publications Regulation Research Research Personnel Role Schizophrenia Social Behavior Societies Structure Testing Thyroid Gland Thyroid Hormones Tissues Work autism spectrum disorder base behavioral outcome behavioral phenotyping brain behavior brain morphology circadian circadian pacemaker circadian regulation comorbidity cost design developmental disease dosage epidemiology study epigenome fetal follow-up genome wide association study imprint improved insight male mouse model neonatal brain nervous system disorder neurodevelopment non-genetic novel novel therapeutics programs prospective

项目摘要

The etiology of many neurodevelopmental disorders including autism, schizophrenia and attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental factors may be involved and that the heritability of those conditions is relatively high. Numerous epidemiological and genome-wide association studies in affected populations have identified environmental factors and candidate genes increasing the susceptibility to those conditions. However, those genetic and environmental factors can only account for a small percentage of the clinical cases. This suggests that additional environmental influences remain unidentified, and that the majority of the heritable component of those conditions is of non-genetic origin. We hypothesize that brain overexposure to thyroid hormone during development is an important factor contributing to both the environmental and non-genetic heritable components in the etiology of neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action. In Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3 globally or specifically in neurons for the brain programs of gene expression, adult brain structure and behavior. In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed to an excess of thyroid hormone during development. We will compare the results of developmental gene expression in different parts of the brain with their adult behavior and with the altered epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic inheritance originated in ancestral overexposure to thyroid hormones. Based on the abnormal regulation of circadian rhythms that is typically associated with neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the molecular and developmental basis by which developmental exposure to thyroid hormone excess leads to the abnormal programming of the circadian clock (Specific Aim #3). We anticipate that our work will greatly advance our understanding of the etiology of complex neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental excess of thyroid hormone influences the susceptibility to those conditions directly in the present generation and indirectly in descendants via epigenetic mechanisms of inheritance.

许多神经发育障碍的病因包括自闭症，精神分裂症和

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spermatogonial Dio3 as a potential germ line sensor for thyroid hormone-driven epigenetic inheritance †.

精原细胞 Dio3 作为甲状腺激素驱动的表观遗传的潜在种系传感器 â。

DOI：
10.1093/biolre/ioab089
发表时间：
2021
期刊：
Biology of reproduction
影响因子：
3.6
作者：
Hernandez,Arturo
通讯作者：
Hernandez,Arturo

Adult onset of type 3 deiodinase deficiency in mice alters brain gene expression and increases locomotor activity.

小鼠成年后出现 3 型脱碘酶缺乏症会改变大脑基因表达并增加运动活动。

DOI：
10.1016/j.psyneuen.2019.104439
发表时间：
2019
期刊：
Psychoneuroendocrinology
影响因子：
3.7
作者：
Stohn,JPatrizia;Martinez,MElena;StGermain,DonaldL;Hernandez,Arturo
通讯作者：
Hernandez,Arturo

Toward Epigenetic Profiling of Thyroid Hormone Status.

甲状腺激素状态的表观遗传分析。

DOI：
10.1210/clinem/dgab141
发表时间：
2021
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Hernandez,Arturo
通讯作者：
Hernandez,Arturo

Cerebellar abnormalities in mice lacking type 3 deiodinase and partial reversal of phenotype by deletion of thyroid hormone receptor α1.

缺乏 3 型脱碘酶的小鼠的小脑异常和通过删除甲状腺激素受体 α1 部分逆转表型。

DOI：
10.1210/en.2012-1738
发表时间：
2013
期刊：
Endocrinology
影响因子：
4.8
作者：
Peeters,RobinP;Hernandez,Arturo;Ng,Lily;Ma,Michelle;Sharlin,DavidS;Pandey,Mritunjay;Simonds,WilliamF;StGermain,DonaldL;Forrest,Douglas
通讯作者：
Forrest,Douglas

Thyroid Hormone Deiodination and Action in the Gonads.