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: 3238579
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 14.48万
• 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 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3238579
• 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; recombinant DNA; 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.

以前的调查表明，除了 肠至少20个组织，包括肾脏、胰腺、皮肤和 大脑都有1，25-二羟维生素D3受体 （1，25（OH）2D 3）和/或维生素D诱导的钙结合蛋白 （CaBP），从而表明维生素D在钙中的作用更广泛 代谢而不仅仅是肠道钙吸收。 对象 这一建议的目的是为了更好地了解多个 维生素D内分泌系统的作用，通过研究 哺乳动物28，000 Mr维生素D的功能和调节 依赖CaBP。 将检验两个工作假设：（1） CaBP可能在介导 细胞内钙依赖过程和（2）因子 除了1，25（OH）2D 3之外， mRNA和随后的蛋白质合成。 为了 为了确定CaBP的功能意义， 关于剂量依赖性抑制的初步结果 将追踪Ca++依赖性蛋白激酶的CaBP。 为了 研究CaBP可能参与突触 事件，我们将扩大我们的初步调查结果， 在突触体中存在CaBP，我们将测试 CaBP激活Ca-Mg ATP酶。 我们将使用凝胶覆盖 技术，以确定是否特异性结合蛋白 可以检测和识别。 此外，使用 与CaBP mRNA互补的DNA探针和重组DNA 技术，我们将研究哺乳动物CaBP的调节， 在体内和体外。 CaBP基因表达的变化 将审查和研究有关的发展， 将启动人CaBP的调节。 的核苷酸 将确定CaBP的序列，并研究有关 使用转染的细胞调节CaBP基因表达将是 启动。 很可能， 了解维生素D调节钙稳态， 是通过检测分子水平的变化而得出的。 在这项研究中， 是为了更详细地了解 1，25（OH）2D 3参与许多疾病过程 钙稳态过程异常， 骨软化、骨质疏松和甲状旁腺紊乱 功能 此外，这项研究可能会增加 了解维生素D内分泌系统在 正常的大脑功能以及大脑紊乱， 钙依赖功能。