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

• 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
• 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

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）：