Functional Analysis of the Clp Protease Systems in Chlamydial Growth and Differentiation

Clp 蛋白酶系统在衣原体生长和分化中的功能分析

基本信息

批准号：
10654041
负责人：
Derek James Fisher
金额：
$ 45.55万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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/10654041
关键词：
ATP phosphohydrolase Adult Arginine Asthma Bacillus subtilis Bacteria Binding Sites Biochemical Biological Assay Biology Blindness Cell Cycle Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Chlamydia Chlamydia Infections Chlamydia trachomatis Chronic ClpX protein Complex Cytoplasm Data Dependence Developed Countries Developing Countries Development Differentiation and Growth Disease Drug Targeting Elements Ensure Essential Amino Acids Genes Genetic Genetic Techniques Genetic Transcription Genome Goals Growth Growth and Development function Healthcare Systems Heart Diseases Homeostasis Human Immunologics In Vitro Incidence Infertility Interferon Type II Maps Mediating Metabolic Molecular Chaperones Morbidity - disease rate Morphology Operon Organism Orthologous Gene Oxidation-Reduction Pathogenesis Pathway interactions Patients Pelvic Inflammatory Disease Peptide Hydrolases Peptides Phosphotransferases Pneumonia Process Protein Isoforms Proteins Proteome Proteomics Regulation Reiter Disease Reporting Respiratory Tract Infections Role Sexually Transmitted Diseases Signal Pathway Signal Transduction Stress Symptoms System Therapeutic Therapeutic Agents Trachoma Translating Translations Tryptophan Work antimicrobial biological adaptation to stress design human pathogen in vivo infection burden interest mutant normal microbiota novel novel therapeutics overexpression pathogen pathogenic bacteria phospho-L-arginine protein degradation proteostasis stem therapeutic target tmRNA tool tubal infertility

项目摘要

Project Summary: Functional analysis of the Clp Protease Systems in Chlamydial Growth and Differentiation Chlamydia is an obligate intracellular bacterial pathogen that causes a range of serious diseases in humans. In developed countries, Chlamydia trachomatis is the primary cause of bacterial sexually transmitted infections (STI). Indeed, recent reports from the Centers for Disease Control highlight the increasing incidence of STIs, with chlamydia infections consistently outpacing all other types. In developing countries, C. trachomatis is not only a significant cause of STI, but it is also responsible for the primary cause of infectious preventable blindness, trachoma. The major concern of chlamydial infections is that they are often asymptomatic and undiagnosed, which can lead to chronic sequelae. These include pelvic inflammatory disease, tubal factor infertility, and reactive arthritis for C. trachomatis. Consequently, chlamydial diseases remain a significant burden on health care systems around the world. In adapting to obligate intracellular growth, Chlamydia has significantly reduced its genome size and eliminated genes from various pathways as it relies on the host cell for its metabolic needs. This pathogen has also adapted to alternate between different functional and morphological forms during its normal growth, also referred to as its developmental cycle. These observations, combined with its obligate intracellular dependence, makes Chlamydia a difficult organism with which to work. However, recent development of genetic tools to study chlamydiae mechanistically have significantly enhanced our understanding of this pathogen. This proposal applies a combination of these new genetic techniques and classical biochemical studies to evaluate the role of conserved protease systems in chlamydial growth and pathogenesis. The hypothesis of the proposed work is that Chlamydia uses two separate protease systems to regulate its growth and transition between developmental forms as well as to respond to stress. Major goals of the proposal include (i) characterizing the function of the different protease systems both in vitro and in vivo and (ii) identifying and validating substrates of these protease systems. Results will advance our understanding of this important pathogen and lead to the design of novel therapeutic agents that are specific for Chlamydia. This in turn will allow for minimal effects on normal flora for patients receiving treatment for this highly prevalent disease.

项目摘要：CLP蛋白酶系统在衣原体生长中的功能分析和分化衣原体是一种义务的细胞内细菌病原体，会导致一系列严重疾病人类。在发达国家，沙眼衣原体是细菌性传播的主要原因感染（STI）。确实，疾病控制中心的最新报告突出了发病率的增加 STI，衣原体感染始终超过所有其他类型。在发展中国家，C。气管瘤不仅是STI的重要原因，而且还导致了传染性的主要原因可预防的失明，沙眼。衣原体感染的主要关注点是它们经常是无症状和未诊断，可能导致慢性后遗症。这些包括骨盆炎症疾病，输卵管因子不育症和气管梭菌的反应性关节炎。因此，衣原体疾病在世界各地的医疗保健系统上仍然承担重大负担。为了适应义务细胞内生长，衣原体大大降低了其基因组大小和从各种途径中消除了基因，因为它依靠宿主细胞来代谢需求。这种病原体还适用于在正常生长期间不同功能和形态学形式之间的替代品，也称为其发展周期。这些观察结果，结合了其专有的细胞内依赖性使衣原体成为一个困难的有机体。但是，最近的发展从机理上研究衣原体的遗传工具显着增强了我们对此的理解病原。该提案采用了这些新遗传技术和经典生化的结合评估保守蛋白酶系统在衣原体生长和发病机理中的作用的研究。这拟议工作的假设是衣原体使用两个独立的蛋白酶调节其生长以及发展形式和应对压力之间的过渡。提案的主要目标包括（i）表征体外和体内不同蛋白酶系统的功能以及（ii）识别和验证这些蛋白酶系统的底物。结果将提高我们对这种重要的病原体并导致了针对衣原体特有的新型治疗剂的设计。反过来，这将使接受这种高度普遍治疗的患者对正常菌群产生最小的影响疾病。