FUNCTION OF THE CALCIUM SENSING RECEPTOR IN THE BREAST

乳房钙敏感受体的功能

• 批准号: 7101867
• 负责人: John J Wysolmerski
• 金额: $ 32.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101867
• 关键词: biological fluid transport; calcium binding protein; calcium metabolism; calcium transporting ATPase; cell differentiation; cell proliferation; cell surface receptors; female; genetically modified animals; homeostasis; hormone regulation /control mechanism; ion transport; laboratory mouse; lactation; mammary epithelium; parathyroid hormone related protein; parathyroid hormones; pregnancy; receptor expression

DESCRIPTION (provided by applicant): The extracellular calcium-sensing receptor (CaR) binds and signals in response to Ca++ ions. By coordinating parathyroid hormone (PTH) secretion and renal calcium handling in response to fluctuations in extracellular Ca++, the CaR is critical to maintaining systemic calcium homeostasis. This receptor is also expressed in breast tissue and in breast cancers. We have found that the CaR is highly expressed in the normal mouse mammary gland during lactation, but is not expressed during pregnancy. Activation of the CaR inhibits the production of parathyroid hormone-related protein (PTHrP) by lactating mammary epithelial cells (MECs) both in vitro and in vivo. Furthermore, we have shown that CaR signaling promotes the transepithelial transport of calcium and water into milk. Based on these data, we propose a new paradigm: that the mammary gland becomes a calcium-sensing organ during lactation and actively participates in the regulation of systemic calcium and bone homeostasis. We propose that the CaR increases PTHrP secretion when calcium delivery to the mammary gland falls in order to increase maternal bone resorption, protect against maternal hypocalcemia and restore the supply of calcium for milk production. We also propose that the mammary CaR matches the transport of calcium into milk with the maternal supply of calcium. This would protect against severe hypocaclemia in the mother by reducing demand if supplies of calcium became limiting. Finally, given the loss of CaR expression during pregnancy, a time of intense MEC proliferation, we hypothesize that CaR signaling inhibits MEC proliferation and promotes MEC differentiation. In order to test these hypotheses we propose 4 Specific Aims. Aim 1 will examine mammary PTHrP production, water and calcium transport and maternal bone and mineral metabolism in a mouse model of mammary-specific CaR gene deletion. Aim 2 will examine the regulation of the plasma membrane Ca++/ATPase 2 (PMCA2) by CaR signaling in MECs. Aim 3 will examine the signaling pathways that mediate the mammary CaR's regulation of PTHrP production. Aim 4 will examine the effects of CaR signaling on MEC proliferation by expressing an activated mutant of the CaR in the mammary gland during pregnancy in transgenic mice. We believe that these studies will deepen our understanding of the physiology of the CaR and will contribute to an understanding of both osteoporosis and bone metastases in patients with breast cancer.

描述（由申请人提供）：响应Ca ++离子的细胞外钙感应受体（CAR）结合和信号。通过协调甲状旁腺激素（PTH）分泌和肾钙处理，以响应细胞外Ca ++的波动，该汽车对于维持全身性钙稳态至关重要。该受体在乳腺组织和乳腺癌中也表达。我们发现，该汽车在哺乳期间在正常小鼠乳腺中高度表达，但在怀孕期间未表达。 CAR的激活通过在体外和体内抑制乳腺激素相关蛋白（PTHRP）的产生。此外，我们已经表明，汽车信号传导促进了钙和水的旋转转运。基于这些数据，我们提出了一种新的范式：乳腺在哺乳期间变成了钙感应器官，并积极参与系统性钙和骨稳态的调节。我们建议，当钙递送到乳腺下降时，汽车会增加PTHRP的分泌，以增加母体骨吸收，预防母体低钙血症并恢复牛奶产量的钙供应。我们还建议，乳腺汽车与钙的钙供应与钙的运输匹配。如果钙的供应限制，这将通过减少需求来预防母亲的严重低血压。最后，鉴于怀孕期间汽车表达的丧失，这是MEC增殖的激烈时代，我们假设CAR信号抑制了MEC增殖并促进MEC分化。为了检验这些假设，我们提出了4个具体目标。 AIM 1将在乳腺特异性CAR基因缺失的小鼠模型中检查乳腺PTHRP的产生，水和钙转运以及母体骨和矿物质代谢。 AIM 2将检查MEC中的CAR信号传导对质膜Ca ++/ATPase 2（PMCA2）的调节。 AIM 3将检查介导乳腺CAR对PTHRP生产调节的信号传导途径。 AIM 4将通过在转基因小鼠怀孕期间表达乳腺中汽车的活化突变体来检查汽车信号对MEC增殖的影响。我们认为，这些研究将加深我们对汽车生理学的理解，并有助于理解乳腺癌患者的骨质疏松症和骨转移。