Activation of TGFbeta by a gut pathobiont

这一建议旨在促进对结肠微生物对生长因子调控的新理解。我们 发现鸡溶血性链球菌亚种。溶胆杆菌(SGG)是一种医学上重要的肠道致病菌， 直接激活转化生长因子b(TGFb)，这种激活对致病性很重要 是SGG的。这项提议的目标是确定介导TGFb激活的特定SGG分子。 TGFb是一个具有根本重要性的增长因素。由于它的许多功能，TGFb是一个关键的参与者 在一系列人类疾病(例如，免疫紊乱、纤维化和癌症)中，以及被广泛追求的 心理治疗。对TGFb的监管显然至关重要。动物调节转化生长因子b的机制 多年来受到了强烈的研究关注。相比之下，TGFb的微生物调控还没有得到 经过广泛调查。TGFb以一种不活跃的潜伏复合体的形式分泌，必须经过细胞外 激活以触发下行信令事件。据我们所知，我们的发现是第一次描述 一种具有TGFb激活基因编码因子的结肠微生物。这是一个重大突破 在对TGFb的微生物调控方面探索不足的领域，并呼吁进行进一步的调查，以划定 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 对SGG致病机制的了解。我们的初步结果以及之前报道的体内效应 以及已知的TGFb活性，有力地支持了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的和临床上重要的肿瘤生长因子b机制。 由一种结肠病原体调节。鉴于TGFb和SGG的重要性，以及目前的知识差距， 进一步研究SGG激活TGFb的机制及其病理生物学细节 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 特定的SGG分子对TGFb的激活很重要。遗传学、蛋白质组学和生物化学的结合 将使用各种方法来鉴定特定的SGG分子。这些研究是实现以下目标的关键的第一步 填补了我们关于结肠微生物在疾病中调控TGFb的知识的一个主要空白。新加坡政府 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 这一新的和临床上重要的机制的分子细节以及了解这种激活是如何 有助于SGG的致病性，并影响其所在的寄主环境。建议数 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。

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.