Functions of thyroid hormone in retinal development

甲状腺激素在视网膜发育中的作用

• 批准号: 8939591
• 负责人: Douglas Forrest
• 金额: $ 72.15万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939591
• 关键词: Candidate Disease Gene; Cells; Characteristics; Color; Color Visions; Cone; Defect; Degenerative Disorder; Development; Endocrine system; Enzymes; Gene Duplication; Gene Targeting; Genes; Genetic; Hormonal; Human; Investigation; Iodide Peroxidase; Ligands; Light; Link; Mediating; Modeling; Mus; Nature; Opsin; Pathway interactions; Pattern; Photoreceptors; Population; Protein Isoforms; Retina; Retinal; Retinal Cone; Role; Series; Signal Transduction; Specificity; Staging; System; Testing; Thyroid Diseases; Thyroid Hormone Receptor; Thyroid Hormone Receptor Gene; Thyroid Hormones; Time; Tissues; Vertebrate Photoreceptors; Visible Radiation; Visual; Visual system structure; cell type; insight; mouse model; novel; receptor; retinal progenitor cell; retinal rods; transcription factor

Color vision depends upon the differential expression in retinal cone photoreceptors of opsin photopigments that confer sensitivity to different regions of the visible light spectrum. Most mammalian species are dichromatic and express opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this system but have trichromatic function because of a gene duplication that created another opsin gene for sensitivity to long wave (L, red) light. The mechanisms that differentially pattern opsins are critically important for color vision. However, the underlying signals and genetic controls have remained largely elusive. Our study of the Thrb thyroid hormone receptor gene identified an unexpectedly critical role for a thyroid hormone receptor, TRb2, in the diversification of M and S opsin expression in sub-populations of cones in a mouse model. Deletion of TRb2 results in a loss of M opsin, revealing a key role for TRb2 in opsin patterning. The unexpected nature of this finding raises questions regarding the link between the endocrine and visual systems. Previously, in the study of thyroid disorders in humans or in mammalian model species, the possibility of color visual deficiencies had been largely overlooked. The project aims to investigate how TRb2 and thyroid hormone regulate cone development and to investigate which genes may cooperate with Thrb in the color visual system. Progress: 1. The role of thyroid hormone in modifying the timing and pattern of opsin expression in cone development in a mouse model. We continue to investigate this key question to test the hypothesis that TRb2 and the hormonal ligand is important in modifying cone development, function and survival. In additional studies, we continue to test the consequences of a lack of thyroid hormone at sensitive, early stages of retinal development to indicate possible cone defects that may potentially arise in developmental thyroid disorders. 2. Candidate factors that may cooperate with TRb2 in the development of cone photoreceptors include other transcription factors and at the pre-receptor stage, the deiodinase enzymes that could activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. We continue to investigate the multigenic nature of the controls that direct the development of cone photoreceptors. These studies investigate the importance of mechanisms that both augment as well as constrain thyroid hormone action in the differentiation of specific cell types in immature tissues. 3. Investigation of the target genes that are regulated by TRb2 in retinal development. We continue our studies to identify the downstream genes that mediate thyroid hormone action in the retina. The identification of these critical target genes is expected to reveal insights into mechanisms of action of thyroid hormone and to identify new genes involved in photoreceptor differentiation and potentially also genes that underlie developmental or degenerative diseases of the retina.

彩色视觉取决于视网膜光成像的视网膜光感受器中的差异表达，这些表达赋予了对可见光光谱的不同区域的敏感性。大多数哺乳动物物种都是二分和表达蛋白，以敏感到中等长度（M，绿色）或短（S，蓝色）光的光长度。人类共享该系统，但具有三色功能，因为基因重复产生了另一个opsin基因，以使长波（L，红色）光敏感。差异化的Opsins的机制对于色觉至关重要。但是，基本信号和遗传控制仍然难以捉摸。我们对THRB甲状腺激素受体基因的研究确定了甲状腺激素受体TRB2在小鼠模型中锥形亚群中M和S OPSIN表达的多样化中的意外关键作用。 TRB2的删除会导致M OPSIN的损失，从而揭示了TRB2在Opsin模式中的关键作用。这一发现的意外性质引发了有关内分泌和视觉系统之间联系的问题。以前，在人类或哺乳动物模型物种中甲状腺疾病的研究中，颜色视觉缺陷的可能性在很大程度上被忽略了。该项目旨在研究TRB2和甲状腺激素如何调节锥体发育，并研究哪些基因可以与颜色视觉系统中的THRB合作。进步： 1。甲状腺激素在小鼠模型中锥体发育中OPSIN表达的时间和模式中的作用。 我们继续研究这个关键问题，以检验TRB2和激素配体对于修改锥体发育，功能和生存至关重要的假设。在其他研究中，我们继续测试在敏感的，视网膜发育的早期阶段缺乏甲状腺激素的后果，以表明可能在发育性甲状腺疾病中可能出现的锥缺损。 2。可能与TRB2合作在锥形光感受器开发中可能合作的候选因素包括其他转录因子，在受体前阶段，在关键阶段，可以激活或失活的甲状腺激素的脱发酶。我们继续研究指导锥形感受器发展的对照的多基因性质。这些研究研究了在未成熟组织中特定细胞类型的分化中构成甲状腺激素作用的机制的重要性。 3。对视网膜发育中TRB2调控的靶基因的研究。我们继续研究以识别介导视网膜中甲状腺激素作用的下游基因。预期这些关键靶基因的鉴定会揭示对甲状腺激素作用机理的见解，并鉴定涉及光感受器分化的新基因，并有可能是视网膜发育或退化性疾病构成的基因。