Activation of TGFbeta by a gut pathobiont

肠道病原体激活 TGFbeta

基本信息

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
项目类别：
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

项目摘要

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.

该提案旨在促进对结肠微生物生长因子调节的新认识。我们发现溶没食子链球菌亚种。溶没食子酸杆菌（Sgg），一种医学上重要的肠道病原体，直接激活转化生长因子 b (TGFb)，这种激活对于致病性很重要 Sgg 的。该提案的目标是确定介导 TGFb 激活的特定 Sgg 分子。 TGFb 是一种至关重要的生长因子。由于其多种功能，TGFb 是一个至关重要的角色在一系列人类疾病（例如免疫紊乱、纤维化和癌症）中，以及广泛追求的目标治疗。 TGFb 的调节显然至关重要。动物调节 TGFb 的机制多年来受到了广泛的研究关注。相比之下，微生物对 TGFb 的调节尚未得到证实。广泛调查。 TGFb 作为无活性的潜在复合物分泌，必须经过细胞外激活以触发下游信令事件。据我们所知，我们的发现是第一个描述具有 TGFb 激活基因编码因子的结肠微生物。这是一个重大突破 TGFb 的微生物调节尚未得到充分探索，需要进一步研究来描述负责 TGFb 激活的特定 Sgg 分子。拟议的研究进一步推进了有限的 Sgg致病机制的知识。我们的初步结果以及之前报道的体内效果 Sgg 的活性和 TGFb 的已知活性强烈支持这样的观点，即 Sgg 激活 TGFb 对于其致病性。总而言之，我们的研究结果揭示了 TGFb 的一种新颖且具有临床意义的机制结肠病原体的调节。鉴于 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 激活 TGFb 的机制以及详细的病理生物学这种激活的后果应该是高度优先的。该提案的主要目标是确定对 TGFb 激活很重要的特定 Sgg 分子。遗传学、蛋白质组学和生物化学的结合方法将用于识别特定的 Sgg 分子。这些研究是迈向关键的第一步填补了我们关于疾病中结肠微生物调节 TGFb 的知识的重大空白。 SGG 这里确定的分子将为未来的研究提供重要的信息和必要的工具，以阐明这种新颖且具有临床意义的机制的分子细节，并了解这种激活是如何进行的有助于 Sgg 的致病性并影响其所在的宿主环境。拟议的研究将与阿拉巴马大学伯明翰分校的乔安妮·墨菲·乌尔里希合作进行。