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.
Thyroid hormone is essential for normal brain development and for brain function in the adult. Traumatic brain injury (TBI) is associated with reduced levels of triiodothyronine (T3) in the serum as well as in the brain. Recovery from acute and chronic traumatic brain injury (TBI) involves stimulation of some of the same pathways important for brain development. Understanding the role of thyroid hormone in these processes may result in treatments to promote neural preservation and recovery after brain injury. Hypothyroidism is common among women veterans and the elderly. Hypothyroidism is associated with a range of disorders of brain function. Understanding the mechanisms regulating thyroid hormone action in the brain may lead to improved treatments for disorders of mood and cognitive function.
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