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Protist Oxygen Sensing in Human Disease Protist Oxygen Sensing in Human Disease

人类疾病中的原生生物氧传感人类疾病中的原生生物氧传感

基本信息

批准号：
10651752
负责人：
Ira J Blader
金额：
$ 63.45万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651752
关键词：
Address Aerobic American Amino Acids Binding Proteins Biochemical Biological Assay Blood Brain CUL1 gene Calcium Cell Survival Cell physiology Cells Cellular Stress Characteristics Complex Cues Cullin Proteins Cyst Data Development Dictyostelium Differentiation and Growth Disease Distant Environment Essential Amino Acids Exposure to F-Box Proteins Face Fetus Goals Growth Heart Homeostasis Hydroxylation Hypoxia Hypoxia Inducible Factor Immune response Immunocompromised Host In Vitro Infection Interferon Type II Knowledge Learning Life Ligase Lung Mediating Medical Metabolic Modification Muscle Names Nutrient Organism Oxygen Parasites Pathway interactions Peptide Elongation Factor 2 Phosphorylation Phosphotransferases Polyubiquitin Procollagen-Proline Dioxygenase Proliferating Proline Protein Biosynthesis Proteins Proteome Protozoa Publishing RBX1 gene Resistance Retina Shapes Stream Stress Testing Tissues Toxoplasma Toxoplasma gondii Ubiquitin Ubiquitination Virulence Work cytokine extracellular genome analysis human disease in vivo mutant new therapeutic target novel therapeutics pathogen phyA phytochrome phyB phytochrome recruit response transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

Sensing and responding to changes in environmental oxygen is critical for aerobic organisms. Metazoans accomplish this by destabilizing a transcription factor called hypoxia inducible factor (HIF) in oxygen sufficiency. This is achieved by an oxygen-dependent prolyl 4-hydroxylase (PHD) that hydroxylates proline residues in the HIF-1α transcription factor that targets it for ubiquitin-dependent proteasomal degradation. Protozoans have PHDs but lack HIF and thus respond to changes in oxygen differently and we use the evolutionary distant protists Dictyostelium and Toxoplasma to address this question. Initial studies in Dictyostelium revealed that its PHD, DdPHYa, modifies a proline in Skp1, which is a component of the Skp1/Cullin1/F-box protein/Rbx1 polyubiquitin ligase complex. Skp1 prolyl hydroxylation does not affect its stability, but allows it to be modified by a pentasaccharide that acts to alter the repertoire of associated F- Box proteins. Genome analysis and biochemical assays demonstrated that this Skp1 modification pathway is conserved in the protozoan parasite Toxoplasma, but not in metazoans. Loss of Toxoplasma PHYa leads decreases virulence in vivo and decreased growth in vitro under limited O2 and amino acid conditions. Unlike Dictyostelium, Toxoplasma expresses a second PHD, PHYb, which is required for colonization of oxygen rich tissues as well as Toxoplasma growth at high oxygen. In contrast to PHYa, PHYb functions by regulating elongation during protein synthesis and specifically does so at elevated O2 levels. Because of its medical importance, we will focus on Toxoplasma and pursue three specific aims: i) Determine how PHYa mediates growth at low oxygen and amino acids; ii) Define how PHYb regulates elongation; and iii) Test whether PHYa and PHYb work in tandem as an oxygen-sensing rheostat to grow in whatever oxygen tension in encounters as it infects a host and causes disease.

对环境氧气变化的感知和反应对于需氧生物后生动物通过使转录不稳定来实现这一点缺氧诱导因子（HIF）是一种重要的缺氧诱导因子。实现这一点通过氧依赖性脯氨酰4-羟化酶（PHD）羟化脯氨酸 HIF-1α转录因子中的一个残基，靶向它进行泛素依赖性的蛋白酶体降解原生动物有PHD，但缺乏HIF，氧气的变化，我们使用进化中的远距离原生生物网骨藻和弓形虫来解决这个问题。初步研究 Dictyosteopathy揭示了它的PHD，DdPHYa，修饰Skp 1中的脯氨酸，是Skp 1/Cullin 1/F-box蛋白/Rbx 1多聚泛素连接酶的组分复杂. Skp 1脯氨酰羟基化不影响其稳定性，但允许其被被五糖修饰，其作用是改变相关F- 盒蛋白。基因组分析和生化检测表明， Skp 1修饰途径在原生动物寄生虫弓形虫中是保守的，但在后生动物中没有。弓形虫PHYa基因缺失导致致病力降低在有限的O2和氨基酸条件下，体内和体外生长减少。与网骨藻不同，弓形虫表达第二个PHD，PHYb，所需的富氧组织定植以及弓形虫生长，高氧与PHYa相反，PHYb通过调节伸长来发挥功能在蛋白质合成过程中，特别是在氧气水平升高时。因为由于其医学重要性，我们将重点关注弓形虫，并寻求三个具体的目的：i）确定PHYa如何在低氧和氨基酸下介导生长; ii）定义PHYb如何调节伸长;以及作为一个氧气感应变阻器，当它感染宿主并导致疾病时，接触中的紧张局势。