Ttp And Related Proteins In Inflammatory Diseases

炎症性疾病中的 Ttp 和相关蛋白

基本信息

批准号：
7734505
负责人：
Perry J Blackshear
金额：
$ 209.09万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7734505
关键词：
3&apos Untranslated Regions Acquired Immunodeficiency Syndrome Anabolism Arthritis Binding Biochemical Biological Assay Cell Nucleus Cells Cessation of life Chronic Class Complex Crohn&apos s disease Cytosol Dermatitis Disease Elements Evaluation Excision Family Family member Gene Expression Profile Gene Family Genes Genetic Polymorphism Genetic Transcription Genome Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Health Human Inflammation Inflammatory Knock-out Knockout Mice Lead Malignant Neoplasms Mediating Messenger RNA Mus Numbers Organism Pathway interactions Pharmaceutical Preparations Phenotype Physiological Poly(A) Tail Process Proteins Rate Regulation Rheumatoid Arthritis Rodent Screening procedure Serine Stimulus Syndrome TIS11 protein Thinking Time Tumor Necrosis Factor-alpha Tumor Necrosis Factors Variant Writing ZFP36L2 gene Zinc Fingers drug development human TNF protein human ZFP36L2 protein inhibitor/antagonist insight interest mRNA Transcript Degradation macrophage man member novel prototype response small molecule thymidine 5&apos -triphosphate wasting

项目摘要

Tristetraprolin, or TTP, is the prototype of a small family of three known CCCH tandem zinc finger proteins; other known human members of this class are ZFP36L1 and ZFP36L2, while rodents express an additional protein, ZFP36L3. TTP is the best studied member of this family. It is rapidly induced, translocated from the nucleus to the cytosol, and is phosphorylated on serine residues in response to a variety of growth factors and inflammatory stimuli. Mice deficient in TTP develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death; most aspects of the syndrome are due to an excess of circulating tumor necrosis factor (TNF). TNF is over-produced by macrophages derived from these knockout mice, due to an increase in the stability of its mRNA. Conversely, TTP has been found to bind to and promote the degradation of this mRNA as well as that encoding granulocyte-macrophage colony-stimulating factor (GM-CSF). More recent studies have identified the initial process regulated by TTP as the deadenylation of the mRNA, or removal of its poly(A) tail, thought to be the rate limiting step in mammalian mRNA turnover. Current studies are using a recently developed cell-free TTP-dependent deadenylation assay to try to determine the mechanism of this effect. In addition, attempts are underway to utilize this novel pathway regulating TNF expression as a target for new drugs for the treatment of TNF excess diseases, such as rheumatoid arthritis, Crohns disease, AIDS, cancer and others. Similarly, inhibitors of the interaction between TTP and GM-CSF mRNA may be useful treatments for granulocytopenic diseases. A number of polymorphisms in the TTP gene and related genes have been determined through the NIEHS Environmental Genome Project, and studies are underway that will attempt to correlate these changes with human phenotypes. Finally, within the past several years knockout mice have been generated for the other two TTP-related genes common to mice and humans, and ongoing evaluation of their phenotypes should provide new insights into the physiological importance of this interesting gene family. A knockout for the fourth rodent family member, ZFP36L3, is nearing completion at the time of this writing.

Tristetraprolin或TTP是三个已知CCCH串联锌指蛋白的小家族的原型。该类别的其他已知人类成员是ZFP36L1和ZFP36L2，而啮齿动物表达了另一种蛋白质ZFP36L3。 TTP是这个家庭中最好的成员。它是迅速诱导的，从细胞核转移到细胞质，并响应各种生长因子和炎症刺激而在丝氨酸残基上磷酸化。缺乏TTP的小鼠患有一种复杂的综合征，该综合征由关节炎，浪费，皮炎和早期死亡组成。该综合征的大多数方面是由于循环肿瘤坏死因子（TNF）过量引起的。由于其mRNA的稳定性提高，TNF由这些敲除小鼠产生的巨噬细胞过多。相反，已经发现TTP与该mRNA的降解以及编码粒细胞巨噬细胞刺激因子（GM-CSF）结合并促进降解。最近的研究确定了由TTP调节的初始过程是mRNA的苯基化或去除其poly（a）尾巴，被认为是哺乳动物mRNA转换的速率限制步骤。当前的研究使用了最近开发的无细胞TTP依赖性的二苯基化测定法来确定这种作用的机制。此外，正在尝试利用这种调节TNF表达的新途径作为治疗TNF多余疾病的新药物的目标，例如类风湿关节炎，克罗恩斯疾病，艾滋病，癌症等。同样，TTP和GM-CSF mRNA之间相互作用的抑制剂可能是对粒细胞减少性疾病的有用治疗方法。 TTP基因和相关基因中的许多多态性已通过NIEHS环境基因组项目确定，并且正在进行研究，这些研究将试图将这些变化与人类表型相关联。最后，在过去的几年中，对小鼠和人类共有的其他两个与TTP相关的基因产生了基因敲除小鼠，并且对其表型的持续评估应提供对这个有趣基因家族的生理重要性的新见解。在撰写本文时，第四个啮齿动物家庭成员ZFP36L3的淘汰赛即将完成。