Anatomical and Functional Analysis of POMC Neuronal Rescue by Tanycytes

Tanycytes 拯救 POMC 神经元的解剖学和功能分析

• 批准号: 8947556
• 负责人: RONALD Michael LECHAN
• 金额: $ 20.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8947556
• 关键词: Address; Adult; Aging; Alleles; Animals; Anterior Pituitary Gland; Appetite Regulation; Award; Blood; Blood Circulation; Body Composition; Body Weight; Brain; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Cerebrospinal Fluid; Eating; Embryo; Etiology; Floor; Food Energy; Food Intake Regulation; Funding; Generations; Genes; Genetic; Genetic Recombination; Goals; Grant; Growth; Histocytochemistry; Homeostasis; Hypothalamic structure; Immune Sera; In Situ Hybridization; Label; Laboratories; Leptin; Location; Maps; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Mus; Neurites; Neurobiology; Neuroglia; Neurons; Neurosecretory Systems; Neurotransmitters; Obesity; Perikaryon; Phenotype; Population; Presynaptic Terminals; Pro-Opiomelanocortin; Property; Regulation; Research; Research Personnel; Research Project Grants; Role; Signal Transduction; Specificity; Stem cells; Structure of nucleus infundibularis hypothalami; System; Tamoxifen; Testing; Third ventricle structure; Thyroid Function Tests; Transgenic Mice; Vimentin; Work; age related; aging brain; base; blood glucose regulation; energy balance; feeding; high reward; high risk; immunocytochemistry; immunoreactivity; insight; irradiation; man; mature animal; median eminence; mouse model; novel; novel strategies; offspring; postnatal; public health relevance; recombinase; relating to nervous system; response; senescence; stem

 DESCRIPTION (provided by applicant): Senescence of POMC neurons is believed to contribute to the etiology of age-related obesity. As we have identified tanycytes to express POMC in the adult brain and recent evidence indicates that tanycytes have stem cell-like properties and can serve as progenitor cells for hypothalamic neurons, we hypothesize that tanycytes are capable of differentiating into POMC neurons in the mediobasal hypothalamus and potentially could restore failing POMC neurons in the aging brain. To begin to test this hypothesis, we propose to use the R21 exploratory mechanism to determine whether tanycytes can generate POMC neurons in the postnatal brain and integrate into the feeding-related circuitry. To perform these studies, a POMC null transgenic mouse model, ArcPomcfneo/fneoKO, which have an obese phenotype due to the loss of POMC in the mediobasal hypothalamus, will be crossed with RaxCreERT2 mice in which Cre-recombinase is expressed exclusively in tanycytes in response to tamoxifen. Therefore, all POMC neurons observed in the offspring of the resulting ArcPomcRaxRE mice can only be derived from tanycytes. We will determine whether these mice show evidence for improvement in metabolic parameters and obesity when tanycyte POMC is reactivated at postnatal day 4 vs. postnatal day 28 over a 4 month observation period. Included in the analysis will be growth, body weight, food intake, body composition, energy balance, glucose homeostasis and thyroid function. At the end of the observation period, animals will be euthanized to determine the number and location of activated POMC neurons in the mediobasal hypothalamus compared to intact and null POMC controls, and whether they migrate to their natural loci in the mediobasal hypothalamus and integrate into the feeding-related circuitry. Tanycyte-derived POMC neurons will also be phenotyped with respect to their expression of neurotransmitters and responsiveness to leptin. These studies are expected to expand the understanding of POMC system neurobiology in the hypothalamic arcuate nucleus and provide new and novel insights into ways the melanocortin system could be regulated to treat obesity and metabolic disorders associated with aging.

 描述（由申请人提供）：POMC 神经元的衰老被认为是导致年龄相关性肥胖的病因，因为我们已经鉴定出在成人大脑中表达 POMC 的单细胞，并且最近的证据表明单细胞具有干细胞样特性并且可以。作为下丘脑神经元的祖细胞，我们发现单细胞能够分化为下丘脑基底内侧的 POMC 神经元，并且有可能恢复衰老过程中衰竭的 POMC 神经元为了开始测试这一假设，我们建议使用 R21 探索机制来确定 tanycytes 是否可以在出生后大脑中产生 POMC 神经元并整合到喂养相关电路中。 ArcPomcfneo/fneoKO 由于中基底层下丘脑 POMC 缺失而具有肥胖表型，将与 RaxCreERT2 小鼠杂交，其中使用 Cre 重组酶因此，在所得 ArcPomcRaxRE 小鼠的后代中观察到的所有 POMC 神经元只能源自 tanycyte，当 tanycyte POMC 重新激活时，我们将确定这些小鼠是否显示出代谢参数和肥胖的证据。在 4 个月的观察期内，产后第 4 天与产后第 28 天的情况包括生长、体重、食物摄入量、身体成分、能量平衡、血糖。在观察期结束时，对动物实施安乐死，以确定与完整和无效 POMC 对照相比，中基底下丘脑中激活的 POMC 神经元的数量和位置，以及它们是否迁移到中基底中的自然位点。这些研究也将根据神经递质的表达和对瘦素的反应来对下丘脑和与进食相关的神经元的整合进行表型分析。预计将扩大对下丘脑弓状核 POMC 系统神经生物学的理解，并为调节黑皮质素系统治疗肥胖和与衰老相关的代谢紊乱的方法提供新的见解。

项目成果

Variable proopiomelanocortin expression in tanycytes of the adult rat hypothalamus and pituitary stalk.

成年大鼠下丘脑和垂体柄的单细胞中阿片黑皮质素原表达可变。

• 发表时间: 2017-02-15
• 作者: Wittmann, Gábor;Farkas, Erzsébet;Szilvásy;Gereben, Balázs;Fekete, Csaba;Lechan, Ronald M
• 通讯作者: Lechan, Ronald M

Prss56 expression in the rodent hypothalamus: Inverse correlation with pro-opiomelanocortin suggests oscillatory gene expression in adult rat tanycytes.

啮齿动物下丘脑中的 Prss56 表达：与阿片黑皮素原呈负相关，表明成年大鼠单细胞中存在振荡基因表达。

• 发表时间: 2018
• 作者: Wittmann, Gábor;Lechan, Ronald M
• 通讯作者: Lechan, Ronald M

Origin of thyrotropin-releasing hormone neurons that innervate the tuberomammillary nuclei.

支配结节乳头核的促甲状腺素释放激素神经元的起源。

• 发表时间: 2022-09
• 影响因子: 3.1
• 作者: Sánchez;Wittmann, Gábor;Menyhért, Judit;Singru, Praful;Gómez;Sánchez;Yáñez;Pimentel;León;Gereben, Balázs;Fekete, Csaba;Charli, Jean
• 通讯作者: Charli, Jean