Tanycytes and Nonthyroidal Illness

Tanycytes 和非甲状腺疾病

• 批准号: 7842682
• 负责人: RONALD Michael LECHAN
• 金额: $ 15.08万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-10 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842682
• 关键词: Animals; Cell Culture System; Cell Culture Techniques; Cell Line; Cell Nucleus; Cells; Development; Endotoxins; Enzymes; Ependymal Cell; Fasting; Floor; Fluorescence-Activated Cell Sorting; Genes; Homeostasis; Hypothalamic structure; Hypothyroidism; Individual; Infection; Iodothyronine Deiodinase; Microarray Analysis; Mus; Neurons; Neurosecretory Systems; Physiological; Pituitary Gland; Production; Regulation; Role; Structure of nucleus infundibularis hypothalami; Syndrome; Third ventricle structure; Thyroid Gland; Thyroid Hormones; Time; Tissues; Transgenic Mice; Triiodothyronine; base; density; diphtheria toxin receptor; falls; feeding; immune activation; laser capture microdissection; median eminence; mouse model; pituitary thyroid axis; prohormone; public health relevance; pyroglutamyl-peptidase II; recombinase; selective expression; tissue culture

DESCRIPTION (provided by applicant): Tanycytes are specialized ependymal cells found in high density along the floor and ventrolateral walls of the third ventricle between the rostral and caudal limits of the hypothalamic median eminence. Little is known about these cells but their expression of type 2 iodothyronine deiodinase (D2), an enzyme critical for conversion of thyroid hormone into its active form, and responsiveness to fasting and endotoxin in several animal species, has raised the possibility that tanycytes are involved in energy homeostasis and contribute to the mechanism by which circulating thyroid hormone levels fall in individuals with severe infection, termed the "nonthyroidal illness syndrome". To facilitate understanding of the importance of tanycytes in neuroendocrine regulation through effects on the hypothalamic-pituitary-thyroid (HPT) axis and feeding-related centers in the arcuate nucleus, we propose to identify tanycytes-specific genes using laser capture microdissection and microarray analysis and develop transgenic mice that express Cre recombinase specifically in tanycytes. These mice will be used to develop a tanycyte cell culture system, and to specifically ablate alpha and/or beta n vivo by developing double transgenic mice after crossing with a Cre-inducible diphtheria toxin receptor mouse line. These studies are expected to generate new information about the biologic importance of tanycytes and their role in neuroendocrine regulation of the HPT axis and in energy homeostasis. PUBLIC HEALTH RELEVANCE: Tanycytes are specialized cells that line the floor and ventrolateral walls of the third ventricle. Compelling evidence suggests they have an important role in generating thyroid hormone due to high expression of type 2 iodothyronine deiodinase, an enzyme critical for conversion of the prohormone, T4, into the biologically active thyroid hormone, T3. We have proposed, therefore, that tanycytes are involved in regulation of the hypothalamic-pituitary-thyroid (HPT) axis and energy homeostasis. To facilitate the study of these cells in neuroendocrine regulation, we will identify tanycyte specific genes by laser capture microdissection and microarray analysis to develop transgenic mice that express Cre recombinase specifically in tanycytes. These mice will be used to develop double transgenic mice in which tanycytes are selectively ablated or marked with GFP to allow isolation by fluorescence-activated cell sorting (FACS) for tissue culture.

描述(申请人提供)：伸展细胞是一种特殊的室管膜细胞，在第三脑室的底部和腹外侧壁，位于下丘脑正中隆起的吻端和尾端之间，密度很高。人们对这些细胞知之甚少，但它们的2型碘甲状腺原氨酸脱碘酶(D2)的表达，以及在几个动物物种中对禁食和内毒素的反应性，增加了张力细胞参与能量平衡的可能性，并有助于严重感染患者循环甲状腺激素水平下降的机制，被称为“非甲状腺疾病综合征”。为了通过对下丘脑-垂体-甲状腺(HPT)轴和弓状核中与摄食相关的中心的影响来促进对Tanycell在神经内分泌调节中的重要性的理解，我们建议使用激光捕获显微切割和微阵列分析来识别Tanycell特异性基因，并开发在Tanycell中特异性表达Cre重组酶的转基因小鼠。这些小鼠将被用来开发Tanycell细胞培养系统，并在与Cre诱导的白喉毒素受体小鼠系杂交后，通过培育双转基因小鼠来特异性地去除体内的α和/或β毒素。这些研究有望产生关于伸展细胞生物学重要性的新信息，以及它们在HPT轴的神经内分泌调节和能量平衡中的作用。与公共卫生相关：张力细胞是一种特殊的细胞，排列在第三脑室的地板和腹外侧壁。令人信服的证据表明，由于2型碘甲状腺原氨酸脱碘酶的高表达，它们在生成甲状腺激素方面发挥着重要作用，这种酶对于将前激素T4转化为生物活性的甲状腺激素T3至关重要。因此，我们提出，伸展细胞参与调节下丘脑-垂体-甲状腺(HPT)轴和能量平衡。为了便于研究这些细胞在神经内分泌调节中的作用，我们将通过激光捕获显微切割和微阵列分析来鉴定tanycell特异性基因，以建立在tanycell中特异性表达Cre重组酶的转基因小鼠。这些小鼠将被用来开发双转基因小鼠，在这些小鼠中，柔韧细胞被选择性地去除或标记GFP，以便通过荧光激活细胞分选(FACS)进行分离，用于组织培养。