REGULATION OF THE MURINE CALCITONIN RECEPTOR GENE

鼠降钙素受体基因的调控

• 批准号: 6375134
• 负责人: DEBORAH Lynn GALSON
• 金额: $ 34.43万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375134
• 关键词: DNA binding protein; RNase protection assay; calcitonin; cell differentiation; dexamethasone; embryonic stem cell; gene targeting; genetic regulation; genetic regulatory element; genetically modified animals; hormone receptor; interleukin 1; laboratory mouse; molecular cloning; osteoclasts; polymerase chain reaction; receptor expression; transcription factor

DESCRIPTION (adapted from the Investigator's abstract): Calcitonin (CT) was originally identified as an endocrine hormone that lowers extracellular calcium by inhibiting osteoclastic bone resorption and enhancing renal calcium excretion. The identification of CT receptors in diverse tissues and cell types and the demonstration of its effects on the developing embryo indicates that CT may serve a more complex and diverse function than its role in regulating homeostasis. The discovery that the calcitonin receptor (CTR) gene is alternatively spliced and that certain CTR isoforms may bind ligands other than CTL provides further insight into the molecular and biochemical basis for this functional diversity. In the proposed studies, the Principal Investigators will 1) Clone and characterize the murine CTR gene and identify the transcription start site(s) in osteoclasts and other mCTR-expressing cell-types. 2) Define the specific and potentially unique regulatory sequences responsible for expression of mCTR expressing cells and tissues and identify the putative transacting transcription factors that bind to these sequences. A variety of experimental approaches will be used to define the factors controlling mCTR expression in osteoclasts and other cell types during development. This will include defining the sequences involved in the regulation of mCTR gene expression by calcitonin (CT) and other hormones (e.g., dexamethasone) or cytokines (e.g., IL-1). It is anticipated that the regulatory factors that control mCTR gene expression in osteoclasts also are involved in the regulation of the expression of other genes that accompany the final stages of osteoclast differentiation and activation. 3) Investigate the developmental regulation of the mCTR gene. The temporal and cell-specific pattern of mCTR gene expression will be documented, and then transgenic mCTR-lacZ reporter mice will be used to analyzed the relevance of the regulatory regions identified in Aim 2 and to define any other sequences that may be important for developmentally correct expression in vivo. 4) Determine the effect of targeted disruption of the mCTR gene on osteoclasts and other mCTR-expression tissues, and on mouse development. The Principal Investigator and her colleagues and her colleagues will generate transgenic mice with a targeted disruption of the mCTR gene. In addition, they will develop ES cell differentiation techniques to generate osteoclasts from E cells for studying the regulation of mCTR gene expression during osteoclast differentiation and development.

描述（改编自研究者的摘要）：降钙素 (CT) 最初被认为是一种内分泌激素，可以降低 通过抑制破骨细胞的骨吸收和细胞外钙 增强肾钙排泄。 CT受体的鉴定 不同的组织和细胞类型及其对 发育中的胚胎表明 CT 可以服务于更复杂和多样化的 其功能多于其调节体内平衡的作用。该发现表明 降钙素受体（CTR）基因是选择性剪接的，并且某些 CTR 亚型可能结合 CTL 以外的配体，提供了进一步的见解 这种功能多样性的分子和生化基础。在 拟议的研究，主要研究人员将 1) 克隆和 表征小鼠 CTR 基因并识别转录起始点 破骨细胞和其他表达 mCTR 的细胞类型中的位点。 2) 定义 特定且可能独特的调控序列负责 mCTR 表达细胞和组织的表达并确定假定的 处理与这些序列结合的转录因子。品种齐全 实验方法将用于定义控制因素 mCTR 在发育过程中破骨细胞和其他细胞类型中的表达。 这将包括定义参与调节的序列 降钙素 (CT) 和其他激素（例如， 地塞米松）或细胞因子（例如 IL-1）。预计 控制破骨细胞中 mCTR 基因表达的调节因子也 参与其他基因表达的调节 伴随破骨细胞分化和激活的最后阶段。 3) 研究mCTR基因的发育调控。时间性的 mCTR 基因表达的细胞特异性模式将被记录下来，并且 然后转基因 mCTR-lacZ 报告小鼠将用于分析 目标 2 中确定的监管区域的相关性并定义任何 对于发育正确可能很重要的其他序列 体内表达。 4) 确定有针对性的破坏的效果 破骨细胞和其他 mCTR 表达组织以及小鼠上的 mCTR 基因 发展。首席研究员和她的同事以及她的 同事们将培育出转基因小鼠，其有针对性地破坏 mCTR 基因。此外，他们还将开发 ES 细胞分化 从 E 细胞生成破骨细胞的技术用于研究 破骨细胞分化过程中 mCTR 基因表达的调控 发展。

项目成果

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo.

• DOI: 10.1083/jcb.200312135
• 发表时间: 2004-02-16
• 期刊: The Journal of cell biology
• 作者: Dacquin R;Davey RA;Laplace C;Levasseur R;Morris HA;Goldring SR;Gebre-Medhin S;Galson DL;Zajac JD;Karsenty G
• 通讯作者: Karsenty G

The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption.

• DOI: 10.1186/ar134
• 发表时间: 2001
• 期刊: Arthritis research
• 作者: Gravallese EM;Galson DL;Goldring SR;Auron PE
• 通讯作者: Auron PE

Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos

• DOI: 10.1074/jbc.m313973200
• 发表时间: 2004-06-18
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Matsuo, K;Galson, DL;Wagner, EF
• 通讯作者: Wagner, EF