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

• 批准号: 10501967
• 负责人: Derek James Fisher
• 金额: $ 25.12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10501967
• 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; 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; Lead; Mediating; Metabolic; Molecular Chaperones; Morbidity - disease rate; Morphology; Operon; Organism; Orthologous Gene; Oxidation-Reduction; Oxides; 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

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：衣原体生长和衣原体生长过程中CLP蛋白系统的功能分析 差异化 衣原体是一种专性的细胞内细菌病原体，在 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)。事实上，最近来自疾病控制中心的报告强调了发病率的增加 性传播感染中，衣原体感染的速度一直高于所有其他类型。在发展中国家，C. 沙眼衣原体不仅是性传播感染的重要原因，也是感染性疾病的主要原因。 可预防的失明，沙眼。衣原体感染的主要问题是，他们经常 无症状和未确诊，可导致慢性后遗症。这些疾病包括盆腔炎 沙眼衣原体的疾病、输卵管因素不孕和反应性关节炎。因此，衣原体疾病 仍然是世界各地卫生保健系统的重大负担。 在适应细胞内专性生长的过程中，衣原体显著缩小了其基因组大小，并 消除了各种途径的基因，因为它依赖宿主细胞满足其新陈代谢需求。这种病原体 在其正常生长过程中也适应于在不同的功能和形态形式之间切换， 也被称为其发育周期。这些观察结果，结合其专属的细胞内 依赖性，使衣原体成为一个难以对付的有机体。然而，最近的发展 从机制上研究衣原体的遗传工具极大地加强了我们对此的理解。 病原体。这一建议应用了这些新的基因技术和经典的生化技术的组合。 研究评价保守的蛋白水解酶系统在衣原体生长和发病中的作用。这个 拟议工作的假设是衣原体使用两个独立的蛋白酶系统来调节其生长 以及在发育形式之间的转换以及对压力的反应。提案的主要目标 包括(I)体外和体内不同的蛋白水解酶系统的功能特征和(Ii) 鉴定和验证这些酶系统的底物。结果将促进我们对 这是一种重要的病原体，导致了针对衣原体的新型治疗药物的设计。 这反过来将允许对接受高度流行的这种疾病治疗的患者的正常菌群产生最小的影响。 疾病。