CA++ BINDING PROTEINS AND THE VITAMIN D ENDOCRINE SYSTEM

CA 结合蛋白和维生素 D 内分泌系统

• 批准号: 3238578
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 14.63万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-10 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3238578
• 关键词: 1,25 dihydroxycholecalciferol; adenosinetriphosphatase; calcium binding protein; calcium metabolism; endocrine gland /system; gastrointestinal absorption /transport; gene expression; growth /development; homeostasis; laboratory rat; magnesium; messenger RNA; osteomalacia; osteoporosis; parathyroid disorder; protein kinase; synapses; synaptosomes; transfection

Previous investigations have demonstrated that besides the intestine at least 20 tissues including kidney, pancreas, skin and brain all have receptors for 1,25dihydroxyvitamin D3 (1,25(OH)2D3) and/or a vitamin D induced calcium binding protein (CaBP), thus suggesting a wider role for vitamin D in calcium metabolism than merely intestinal calcium absorption. The object of this proposal is to obtain a better understanding of the multiple actions of the vitamin D endocrine system by studying the function and regulation of the mammalian 28,000 Mr vitamin D dependent CaBP. Two working hypotheses will be tested: (1) that CaBP may have an important fundamental role in mediating intracellular calcium dependent processes and (2) that factors other than or in addition to 1,25(OH)2D3 may modulate CaBP mRNA and the subsequent synthesis of the protein. In an effort to establish the functional significance of CaBP, provocative preliminary results concerning a dose-dependent inhibition by CaBP of Ca++ dependent protein kinase will be pursued. In order to examine the possibility that CaBP may participate in synaptic events, we will extend our preliminary findings concerning the presence of CaBP in synaptosomes and we will test the ability of CaBP to activate Ca-Mg ATPase. We will use the gel overlay technique in order to determine whether specific binding proteins for CaBP can be detected and identified. In addition, using the DNA probe complementary to CaBP mRNA and recombinant DNA techniques, we will study the regulation of mammalian CaBP both in vivo and in vitro. Changes in CaBP gene expression during development will be examined and studies concerning the regulation of human CaBP will be initiated. The nucleotide sequence of CaBP will be determined and studies concerning the regulation of CaBP gene expression using transfected cells will be initiated. It is likely that important advances to the understanding of vitamin D regulated calcium homeostasis can be made by examining molecular level changes. Implicit in this study is facilitation of a more detailed understanding of how 1,25(OH)2D3 is involved in the many disease processes involved with abnormalities in the calcium homeostatic process such as osteomalacia, osteoporosis and perturbations of parathyroid function. Additionally, this study may lead to an increased understanding of the role of the vitamin D endocrine system in normal brain function as well as in brain disorder involving calcium dependent functions.

此前的调查表明，除了 肠道至少20个组织，包括肾、胰腺、皮肤和 大脑都有1，25二羟基维生素D3的受体 (1，25(OH)2D3)和/或维生素D诱导的钙结合蛋白 (CABP)，因此表明维生素D在钙中的作用更广泛 新陈代谢不仅仅是肠道钙的吸收。该对象 这一建议的目的是为了更好地了解 通过研究维生素D内分泌系统的作用 哺乳动物28,000 mR维生素D的功能与调控 依从性CABP。将检验两个可行的假设：(1) CABP可能在调解过程中发挥重要的基础性作用 细胞内钙依赖过程和(2)该因子 不同于1，25(OH)2D3的或除1，25(OH)2D3之外的可以调制CABP 信使核糖核酸和随后蛋白质的合成。在一次努力中 确立CABP的功能意义，具有挑衅性 一种剂量依赖性抑制作用的初步结果 将继续进行钙依赖蛋白激酶的CABP研究。按顺序 探讨CABP参与突触的可能性 事件发生后，我们将扩大我们关于 CABP在突触体中的存在，我们将测试 CaBP激活钙-镁ATPase。我们将使用凝胶覆盖 技术以确定特定结合蛋白是否 对于CABP可以被检测和识别。此外，使用 互补于CABP mRNA和重组DNA的DNA探针 技术，我们将研究哺乳动物CABP的调节两者 在体内和体外。CABP基因表达的变化 将审查发展并研究关于 将启动对人CABP的监管。核苷酸 将确定CABP的序列并对其进行研究 利用转基因细胞调控CABP基因表达将是 已启动。这很可能是对 了解维生素D调节的钙稳态可以 通过检查分子水平的变化而产生的。在这项研究中隐含 是否有助于更详细地了解 1，25(OH)2D3参与多种疾病过程 在钙稳态过程中出现异常，如 骨软化、骨质疏松症与甲状旁腺功能紊乱 功能。此外，这项研究可能会导致 了解维生素D内分泌系统在 正常的大脑功能以及涉及的大脑障碍 钙依赖功能。