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（由申请人提供）：伸展细胞是特化室管膜细胞，在下丘脑正中隆起的吻侧和尾侧界限之间的第三脑室底和腹外侧壁沿着高密度分布。关于这些细胞知之甚少，但它们表达2型碘甲腺原氨酸脱碘酶（D2），一种在几种动物物种中将甲状腺激素转化为其活性形式以及对禁食和内毒素的反应性至关重要的酶，已经提出了这样的可能性，即伸长细胞参与能量稳态并有助于严重感染个体循环甲状腺激素水平下降的机制，称为“非甲状腺疾病综合征”。为了便于理解的重要性，通过影响下丘脑-垂体-甲状腺（HPT）轴和摄食相关的中心在弓状核的神经内分泌调节的伸长细胞，我们建议确定伸长细胞特异性基因，使用激光捕获显微切割和微阵列分析和开发转基因小鼠表达Cre重组酶特异性在伸长细胞。这些小鼠将用于开发弹性细胞培养系统，并通过与Cre诱导型白喉毒素受体小鼠系杂交后开发双转基因小鼠来特异性体内消除α和/或β。这些研究有望产生新的信息的生物学重要性的伸长细胞和它们的作用，在神经内分泌调节的HPT轴和能量稳态。公共卫生相关性：伸展细胞是排列在第三脑室底部和腹外侧壁的特化细胞。令人信服的证据表明，由于2型碘甲腺原氨酸脱碘酶的高表达，它们在产生甲状腺激素方面具有重要作用，2型碘甲腺原氨酸脱碘酶是一种将激素原T4转化为生物活性甲状腺激素T3的关键酶。因此，我们提出，伸长细胞参与调节下丘脑-垂体-甲状腺（HPT）轴和能量稳态。为了促进这些细胞在神经内分泌调节的研究，我们将通过激光捕获显微切割和微阵列分析来识别伸长细胞特异性基因，以开发在伸长细胞中特异性表达Cre重组酶的转基因小鼠。这些小鼠将用于开发双转基因小鼠，其中选择性消融或用GFP标记伸长细胞，以允许通过荧光激活细胞分选（FACS）分离用于组织培养。