Thyroid Hormone and Retinoic Acid Regulation of Gene Expression

甲状腺激素和视黄酸对基因表达的调节

基本信息

批准号：
8974308
负责人：
GREGORY A BRENT
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974308
关键词：
Acute Adult Allan-Herndon-Dudley syndrome Apoptosis Area Binding Biological Preservation Brain Brain Diseases Brain Injuries Brain region Calmodulin Candidate Disease Gene Cell Line Cell model ChIP-seq Chickens Chronic Development Differentiation and Growth ES Cell Line Elderly Embryo Enzymes Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Gene Mutation Gene Targeting Genes Genetic Goals Grant Health Human Hypothyroidism Hypoxia In Vitro Individual Injury Iodide Peroxidase Lead Ligands Link MAP Kinase Gene MEKs Mediating Messenger RNA Metabolic Pathway Modeling Modification Mood Disorders Mus Neurologic Deficit Neuronal Differentiation Neurons Nuclear Ovalbumin Pathway interactions Pattern Phosphotransferases Process Profound Mental Retardation Protein Isoforms Recovery Refractory Regulation Reporting Rodent Rodent Model Role Sampling Serum Signal Transduction Pathway Signaling Protein Specimen System Techniques Testing Thyroid Gland Thyroid Hormone Receptor Thyroid Hormones Thyroxine Traumatic Brain Injury Tretinoin Triiodothyronine Veterans Woman base cognitive function embryonic stem cell genetic approach genome-wide hippocampal pyramidal neuron hormone analog improved in vitro Model in vivo inhibitor/antagonist knock-down nerve injury nerve stem cell neural growth neurodevelopment neuron loss neuronal growth neuronal patterning neuronal survival novel receptor binding relating to nervous system response response to injury stem therapeutic target tool transcription factor transcription factor USF transport inhibitor type 2 deiodinase (D2)uptake

项目摘要

DESCRIPTION (provided by applicant): Triiodothyronine (T3) and retinoic acid (RA) are essential for normal neuronal differentiation and growth. We have utilized neuronal cell lines, and embryonic stem (ES) cells differentiated into neurons, to identify T3 and RA gene targets. Thyroid hormone receptor (TR) � is the predominant isoform expressed in neurons and has features distinct from those of TR�. In the previous grant period we identified a link between RA and T3 in neural development. RA stimulates expression of the Monocarboxylate Transporter 8 (Mct8) thyroid hormone transporter, which in turn promotes neuronal T3 uptake. Profound mental retardation and neurologic deficits are reported in humans with gene mutations that inactivate Mct8, Allan-Herndon-Dudley Syndrome, and these individuals are refractory to treatment with T3. Traumatic Brain Injury (TBI) models show reduced levels of T3 in the serum and brain. This project will focus on the role of T3 and RA in promoting neural growth and differentiation as well as recovery from injury. We will identify the mechanisms of T3 and RA gene regulation and modulation of signal transduction pathways. We will determine the functional role of thyroid transporters, especially MCT8 and MCT10, and their influence on neuronal growth, differentiation, and neuron-specific gene expression. We have developed a technique to differentiate mouse ES cells into pyramidal neurons, a unique model to study T3 action in the brain. We will also study gene expression in specific brain areas of specimens from rodent models of acute and chronic TBI. We will use thyroid transport inhibitors and transporter mRNA knockdowns to determine the functional importance of T3 transport. The thyroid hormone analog, DITPA, does not require the Mct8 neural transporter to enter neurons and will be a complimentary tool to probe the importance of the thyroid transport. We will use inhibitors and knockdowns of pathway components to determine the role of the Wnt/� catenin and MEK/ERK MAPK pathways in regulation of neuronal proliferation and thyroid hormone transport. We will utilize genetic approaches to determine the role of TR� and TR� on T3-mediated genes to promote neural differentiation, growth and to prolong neuronal survival. We will evaluate known T3-regulated genes in pyramidal neurons important for growth and differentiation, as well as performing a genome-wide ChIP-Seq project, based on TR� binding, to identify new T3-regulated genes. We will determine the role of factors that modulate T3-regulation of neuronal growth and differentiation, including the actions of Chicken Ovalbumin Upstream Transcription Factor (COUP-TF1) and Calmodulin-Dependent Kinase IV (CamKIV). Finally, we will test expression of T3 signaling pathway genes in rodent brain areas after an acute and chronic TBI model. Our hypothesis is that specific actions of RA on signal transduction pathways and T3 on nuclear gene expression promote neuronal differentiation and growth and prolong neuronal survival, and the response to injury may recapitulate the developmental patterns of neuronal growth and differentiation. Our goal is to identify therapeutic targets with the potential to promote neural differentiation and growth in conditions such as TBI.

描述（由申请人提供）：三碘甲状腺氨酸 (T3) 和视黄酸 (RA) 对于正常神经元分化和生长至关重要。我们利用神经元细胞系和分化为神经元的胚胎干 (ES) 细胞来识别 T3 和 RA 基因靶标。 )�是神经元中表达的主要异构体，具有与 TR�不同的特征。在之前的资助期间，我们发现 RA 和 T3 在神经发育中的联系。单羧酸转运蛋白 8 (Mct8) 甲状腺激素转运蛋白，反过来促进神经元 T3 的摄取据报道，具有使 Mct8 失活的基因突变的人类患有艾伦-赫恩登-达德利综合征，并且这些个体对治疗无效。 T3。创伤性脑损伤 (TBI) 模型显示血清和大脑中 T3 水平降低。该项目将重点关注 T3 的作用。 T3 和 RA 在促进神经生长和分化以及损伤恢复中的作用我们将确定 T3 和 RA 基因调节和信号转导途径的调节机制我们将确定甲状腺转运蛋白的功能作用，特别是 MCT8 和 MCT10。它们对神经元生长、分化和神经元特异性基因表达的影响我们开发了一种将小鼠 ES 细胞分化为锥体神经元的技术，这是研究大脑中 T3 作用的独特模型。我们将使用甲状腺转运抑制剂和转运蛋白 mRNA 敲低来确定 T3 转运的功能重要性，DITPA 不需要 Mct8 神经转运蛋白进入神经元。我们将使用抑制剂和通路成分的敲低来确定 Wnt/� 连环蛋白和 MEK/ERK MAPK 通路在神经元调节中的作用。我们将利用遗传方法来确定 TR� 和 TR� 对 T3 介导的基因的作用，以促进神经分化、生长并延长神经元存活。我们将评估锥体神经元中已知的 T3 调节基因。用于生长和分化，以及基于 TR� 结合进行全基因组 ChIP-Seq 项目，以确定新的 T3 调节基因。我们将确定调节 T3 调节神经元生长和分化的因子的作用，包括鸡的动作最后，我们将测试急性和慢性 TBI 模型后啮齿动物大脑区域中 T3 信号通路基因的表达。信号转导途径上的T3和核基因表达上的T3促进神经元分化和生长并延长神经元存活，并且对损伤的反应可能概括神经元生长和分化的发育模式。在 TBI 等情况下具有促进神经分化和生长潜力的治疗靶点。