Activation of TGFbeta by a gut pathobiont

肠道病原体激活 TGFbeta

• 批准号: 10113536
• 负责人: YI XU
• 金额: $ 22.84万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113536
• 关键词: Address; Affect; Alabama; Animals; Area; Attention; Attenuated; Bacteremia; Biochemical; Biological Assay; Biology; Clinical; Collaborations; Colon; Colorectal Cancer; Complement Factor B; Complex; Development; Disease; Endocarditis; Environment; Event; Fibrosis; Future; Gene Deletion; Genes; Genetic; Goals; Growth Factor; Immune System Diseases; Impairment; Infection; Investigation; Knowledge; Life; Malignant Neoplasms; Mediating; Medical; Methods; Microbe; Molecular; Mus; Names; Pathogenicity; Pathology; Positioning Attribute; Protein Analysis; Proteins; Proteomics; Recombinant Proteins; Regulation; Reporting; Research; Signal Pathway; Signal Transduction; Streptococcus; Transforming Growth Factor beta; Transforming Growth Factors; Universities; Work; colon cancer patients; design; experimental study; extracellular; gene complementation; genomic locus; gut colonization; human disease; human pathogen; in vivo; microbial; microbiota; mutant; novel; novel therapeutic intervention; pathobiont; pathogen; prevent; targeted treatment; tool; tumor growth

This proposal aims to advance a new understanding of growth factor regulation by colonic microbes. We discovered that Streptococcus gallolyticus subsp. gallolyticus (Sgg), a medically important gut pathobiont, directly activates transforming growth factor b (TGFb) and that this activation is important for the pathogenicity of Sgg. The goal of this proposal is to identify the specific Sgg molecules that mediate TGFb activation. TGFb is a growth factor of fundamental importance. Due to its many functions, TGFb is a crucial player in a range of human diseases (e.g., immune disorders, fibrosis and cancer) and a widely pursued target for therapy. Regulation of TGFb is clearly of critical importance. The mechanisms by which animals regulate TGFb have received intense research attention over the years. In contrast, microbial regulation of TGFb has not been extensively investigated. TGFb is secreted as an inactive latent complex and must undergo extracellular activation to trigger downstream signaling events. To the best of our knowledge, our finding is the first description of a colonic microbe possessing genetically encoded factors for TGFb activation. This is a major breakthrough in the underexplored area of microbial regulation of TGFb and calls for further investigation to delineate the specific Sgg molecules responsible for TGFb activation. The proposed studies further advance the limited knowledge of Sgg pathogenic mechanisms. Our preliminary results along with previously reported in vivo effects of Sgg and the known activities of TGFb strongly support the idea that TGFb activation by Sgg is important for its pathogenicity. Taken together, our findings reveal a novel and clinically important mechanism of TGFb regulation by a colonic pathobiont. Given the importance of TGFb and Sgg, and the current knowledge gap, further investigations to understand the mechanism of TGFb activation by Sgg and the detailed pathobiological consequences of this activation should be of high priority. The primary goal of this proposal is to identify the specific Sgg molecules important for TGFb activation. A combination of genetic, proteomics and biochemical methods will be used to identify the specific Sgg molecules. These studies constitute a critical first step towards filling a major gap in our knowledge regarding regulation of TGFb by colonic microbes in disease. The Sgg molecules identified here will provide vital information and necessary tools for future studies to elucidate the molecular details of this novel and clinically important mechanism and to understand how this activation contributes to the pathogenicity of Sgg and influences the host environment in which it resides. The proposed studies will be carried out in collaboration with Joanne Murphy-Ullrich, University of Alabama at Birmingham.

该提案旨在提高对结肠微生物的生长因子调节的新理解。我们 发现Gallolyticus subsp链球菌。 Gallolyticus（SGG），一种重要的医学肠道病原体， 直接激活转化生长因子B（TGFB），并且这种激活对于致病性很重要 SGG。该建议的目的是确定介导TGFB激活的特定SGG分子。 TGFB是基本重要性的增长因素。由于其许多功能，TGFB是一个关键的参与者 在一系列人类疾病（例如免疫疾病，纤维化和癌症）中，广泛追求的目标 治疗。 TGFB的调节显然至关重要。动物调节TGFB的机制 多年来，人们一直受到强烈的研究关注。相反，TGFB的微生物调节尚未 经过广泛研究。 TGFB被分泌为一种不活跃的潜在复合物，必须进行细胞外 激活以触发下游信号事件。据我们所知，我们的发现是第一个描述 具有具有遗传编码因子的TGFB激活因子的结肠微生物。这是一个重大突破 在TGFB的微生物调节的未置换区域中，呼吁进一步研究以描绘 负责TGFB激活的特定SGG分子。拟议的研究进一步提高了有限 SGG致病机制的知识。我们的初步结果以及先前报道的体内效应 SGG和TGFB的已知活动强烈支持以下观点：SGG激活TGFB对 它的致病性。综上所述，我们的发现揭示了一种新颖而临床上重要的TGFB机制 结肠病原体调节。考虑到TGFB和SGG的重要性以及当前的知识差距 进一步研究以了解SGG和详细病理学的TGFB激活机制 这种激活的后果应具有很高的优先级。该提议的主要目标是确定 特定的SGG分子对于TGFB激活很重要。遗传，蛋白质组学和生化的结合 方法将用于识别特定的SGG分子。这些研究构成了迈向的关键第一步 填补了我们关于疾病中结肠微生物对TGFB调节的主要差距。 SGG 这里确定的分子将为以后的研究提供重要的信息和必要的工具，以阐明 这种小说和临床上重要机制的分子细节，并了解这种激活如何 有助于SGG的致病性，并影响其居住的宿主环境。提议 研究将与伯明翰阿拉巴马大学的Joanne Murphy-Ullrich合作进行。