MOUSE EXTRACELLULAR CALCIUM SENSING RECEPTOR

细胞外钙稳态是精确调节的， 几种激素与多个靶器官的相互作用。 在 此外，钙本身作用于G蛋白偶联的“钙- 甲状旁腺细胞表面的“感应”受体（CaSR）， 调节甲状旁腺激素（PTH）的分泌。 该受体 也在其他组织中表达，在这些组织中，它的精确功能不那么重要。 定义明确 有两个失活突变拷贝的人类 caSR基因中的基因是严重的高钙血症，大概是因为 钙对PTH分泌的正常抑制作用不再 礼物 CaSR由不同类型的肾脏细胞表达， 其中细胞外钙具有多种作用。 的目的 这一建议是为了阐明CaSR在介导特异性 钙对肾脏的影响，并更好地确定钙的作用， 肾钙受体调节整个动物钙稳态。 这项建议的目的是集中在基因的发展， 改变的小鼠将作为模型， 肾Car的功能 转基因小鼠过度表达CaSR， 将产生肾的粗升支。 这个鼠标 模型应有助于澄清CaSR活化对 调节钙、钠和水的体内平衡。 它还将 有助于确定钙对肾脏的哪些作用是介导的 的CaSR。 此外，CaSR无效突变小鼠的肾功能 将通过遗传学和生理学的结合来研究 方法. 正常情况下，这些基因敲除的老鼠活不过 新生儿期 将CaSR缺陷小鼠与其他突变体杂交 不能对PTH产生高钙反应的小鼠应 产生活的CaSR缺陷小鼠，这将有助于 肾脏和其他组织中CaSR功能的研究。 关于CaSR在肾钙中作用的多种假设 排泄，以及其在介导肾脏对 将研究钙。 阐明CaSR的功能，CaSR是一种新发现的成分， 钙稳态系统，可能会影响到 钙异常疾病的认识与治疗 调节，包括骨质疏松、甲状旁腺功能亢进、肾 结石和高血压

Extracellular calcium homeostasis is precisely regulated by the interaction of several hormones with multiple target organs. In addition, calcium itself acts upon a G-protein-coupled "calcium- sensing" receptor (CaSR) on the he surface of parathyroid cells to regulate the secretion of parathyroid hormone (PTH). This receptor is also expressed in other tissues, where its precise function is less well-defined. Humans with two copies of an inactivating mutation in the caSR gene are severely hypercalcemic, presumably because the normal inhibition of PTH secretion by calcium is no longer present. CaSR is expressed by diverse cell types of the kidney, where extracellular calcium has multiple effects. The purpose of this proposal is to clarify the role of CaSR in mediating specific effects of calcium on the kidney and to better define the role of renal CaSR in regulating whole animal calcium homeostasis. The aims of this proposal focus on the development of genetically altered mice which will serve as models in understanding the function of renal Car. Transgenic mice overexpressing CaSR in the thick ascending limb of the kidney will be generated. This mouse model should help clarify the contribution of CaSR activation to the regulation of calcium, sodium, and water homeostasis. It will also aid in defining which actions of calcium on the kidney are mediated by CaSR. In addition, the renal function of mice with a null mutation in CaSR will be investigated by a combination of genetic and physiologic methods. Normally these ~knockout~ mice do not live past the neonatal period. Crossing CaSR deficient mice with other mutant mice unable to mount a hypercalcemic response to PTH should generate viable CaSR-deficient mice which will aid in the investigation of CaSR function in the kidney and other tissues. Multiple hypotheses regarding the role of CaSR in renal calcium excretion and as well as its role in mediating renal responses to calcium will be investigated. Clarifying the functions of CaSR, a newly identified component of the calcium homeostatic system, will likely have implications for understanding and treatment of diseases of abnormal calcium regulation, including osteoporosis, hyperparathyroidism, kidney stones, and hypertension.