Activation of TGFbeta by a gut pathobiont

该提案旨在促进对结肠微生物对生长因子调节的新理解。我们 发现解没食子链球菌（Streptococcus gallolyticus subsp.）解没食子酸杆菌（Sgg），一种医学上重要的肠道致病菌， 直接激活转化生长因子B（TGF B），并且这种激活对于致病性是重要的 关于SGG该提案的目标是鉴定介导TGF β激活的特定Sgg分子。 TGFb是一种具有根本重要性的生长因子。由于它的许多功能，TGF β是一个至关重要的球员， 在一系列人类疾病中（例如，免疫疾病、纤维化和癌症），以及广泛追求的 疗法TGFb的调节显然至关重要。动物调节TGF b的机制 多年来一直受到研究的关注。相比之下，TGF β的微生物调节尚未被证实。 广泛调查。TGF β作为一种无活性的潜伏复合物分泌，必须经历细胞外 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 一种结肠微生物，它拥有TGF β激活的基因编码因子。这是一个重大突破 在TGF β的微生物调节的未充分探索的领域，并呼吁进一步调查，以描绘 负责TGF β激活的特异性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。我们的初步结果沿着先前报道的体内效应 Sgg和TGF β的已知活性强烈支持这样的观点，即Sgg激活TGF β对于 其致病性。综上所述，我们的研究结果揭示了一个新的和临床上重要的机制，TGF β 结肠致病菌的调节。鉴于TGF β和Sgg的重要性以及目前的知识差距， 进一步研究以了解Sgg激活TGFb的机制和详细的病理生物学作用。 这种激活的后果应该是高度优先的。本提案的主要目标是确定 特异性Sgg分子对TGF β活化很重要。基因、蛋白质组学和生物化学的结合 方法将被用来识别特定的Sgg分子。这些研究是关键的第一步， 填补了我们关于疾病中结肠微生物调节TGF β的知识的主要空白。关于SGG 在此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 这种新的和临床上重要的机制的分子细节，并了解这种激活 有助于Sgg的致病性并影响其所处的宿主环境。拟议 研究将与伯明翰亚拉巴马大学的Joanne Murphy-Ullrich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.