VITAMIN D RESISTANCE: MONKEY TO MAN

维生素 D 抵抗力：从猴子到人

• 批准号: 7413469
• 负责人: John S Adams
• 金额: $ 33.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413469
• 关键词: African; Binding; Binding Proteins; Biochemical; Bone Diseases; Cells; Central America; Cholecalciferol; Complementary DNA; Cytoplasm; DNA Binding; Elements; Family; Gene Expression; Generations; Genes; Genetic Transcription; Geographic Distribution; Hand; Heterogeneous-Nuclear Ribonucleoproteins; Homo sapiens; Hormones; Human; In Vitro; Intestines; Mediating; Messenger RNA; Molecular Cloning; Monkeys; Mus; Mutation; Natural Selections; Nature; Nuclear; Nucleic Acids; Organism; Patients; Phenotype; Planets; Play; Primates; Process; Protein Binding; Protein Overexpression; Proteins; RNA; RNA Binding; RNA Splicing; RXR; Resistance; Response Elements; Role; Single-Stranded DNA; Staging; Sterols; Syndrome; Therapeutic Intervention; Time; Tissues; Transactivation; Transfection; Translation Process; Translations; Ultraviolet B Radiation; Vitamin D; Vitamin D Response Element; Vitamin D3 Receptor; Vitamins; Work; base; ds-DNA; hormone resistance; in vivo; man; novel; nucleic acid binding protein; protein aminoacid sequence; research study; steroid hormone

DESCRIPTION (provided by applicant): Primate species have developed to be the most biologically sophisticated organisms on our planet. Homo sapiens or man, has evolved from ancestral Old World primates inhabiting the African sub-continent and not from New World primates of South and Central America. In the Eocene 50-100 million years ago primordial primates in both the New and Old World were indistinguishable from one another, so why did man arise in the Old and not the New World? We propose that that the answer to this question is that New World primate species, unlike their Old World counterparts, were limited in geographic distribution to the periequatorial regions of the New World as a consequence of the acquired over-expression of a sub-family of nucleic acid binding proteins. These heterogeneous nuclear ribonucleoproteins (hnRNPs), at least one of which the vitamin D response element binding protein (VDRE-BP), competes in trans for binding to the vitamin D response element (VDRE) to squelch vitamin D receptor-directed transactivation. Although now known to be expressed in human as well as in subhuman primate cells, it was not previously known whether the hnRNP-related VDRE-BPs played a comparable role in gene expression in man. With the recent discovery of a human with hnRNP-mediated, VDR-RXR-normal, vitamin D resistance, it is now postulated that the family of hnRNP molecules can also serve as modulators of gene transcription and expression in man. In order to investigate this hypothesis three Specific Aims, representing a natural extension of our work from New World primates to man, will be undertaken: 1] Sequence, clone and functionally characterize the transcriptional squelching potential of the human vitamin D resistance-causing response element binding protein (REBiP); 2] perform forced overexpression of the human REBiP in mouse to recapitulate its capability to generate a rachitic phenotype in vivo; and 3] determine what effects the RNA-DNA binding actions of the human REBiP have on the splicing, processing, translation and function of VDR-regulated gene products. We expect to determine that the hnRNP-related REBiP represents 1] a novel paradigm for the means by which the cell's mRNA-making and -processing machines can be modulated by a single multi-functional protein and 2] a point of potential therapeutic intervention in the action of sterol/steroid hormones on their respective target cells.

描述（由申请人提供）：灵长类动物已发展成为地球上生物学最复杂的生物体。智人或人类是从居住在非洲次大陆的旧世界灵长类动物祖先进化而来的，而不是从南美洲和中美洲的新世界灵长类动物进化而来。在50-1亿年前的始新世，新世界和旧世界的原始灵长类动物彼此无法区分，那么为什么人类出现在旧世界而不是新世界呢？我们认为这个问题的答案是，新世界灵长类物种与旧世界灵长类物种不同，由于获得性过度表达灵长类动物亚科，其地理分布仅限于新世界近赤道地区。核酸结合蛋白。这些异质核核糖核蛋白 (hnRNP)，其中至少一种是维生素 D 反应元件结合蛋白 (VDRE-BP)，以反式竞争与维生素 D 反应元件 (VDRE) 结合，以抑制维生素 D 受体介导的反式激活。尽管现在已知 hnRNP 相关的 VDRE-BP 在人类以及亚人类灵长类动物细胞中表达，但之前并不知道 hnRNP 相关的 VDRE-BP 在人类基因表达中是否发挥了类似的作用。随着最近发现人类具有 hnRNP 介导的、VDR-RXR 正常的维生素 D 抗性，现在推测 hnRNP 分子家族也可以作为人类基因转录和表达的调节剂。 为了研究这一假设，将实现三个具体目标，代表我们的工作从新大陆灵长类动物到人类的自然延伸：1]对人类维生素 D 抗性反应元件的转录抑制潜力进行序列、克隆和功能表征结合蛋白（REBiP）； 2]在小鼠中强制过度表达人REBiP，以重现其在体内产生佝偻病表型的能力； 3]确定人REBiP的RNA-DNA结合作用对VDR调节的基因产物的剪接、加工、翻译和功能有何影响。我们期望确定 hnRNP 相关的 REBiP 代表了 1] 一种新的范例，通过该范例可以通过单个多功能蛋白质来调节细胞的 mRNA 制造和加工机器，以及 2] 潜在的治疗干预点甾醇/类固醇激素对其各自靶细胞的作用。