TGF-beta signaling in schistosomes

描述（由申请人提供）：血吸虫病是由血吸虫属寄生虫引起的疾病，全球有2亿人患病。血吸虫是复杂的后生动物病原体，属于双边门的一个早期分支，即光虫纲。我们对这类动物细胞间通讯的分子基础知之甚少，但有针对性的研究和基因组测序工作表明，毫不奇怪，血吸虫含有一些在高阶后生动物中发现的细胞间信号系统。其中，我们对转化生长因子2 （TGF2）途径特别感兴趣。阐明这一途径在血吸虫生物学中的作用将是本提案的目标。我们对TGF2途径在血吸虫中的作用的核心观点是，我们未能在这些生物体中识别出TGF2配体的基因，这使我们假设血吸虫中的TGF2信号通路进化为接收来自宿主TGF2配体的信号，这一概念被血吸虫TGF2受体可以对人类TGF2配体做出反应的发现所证实。然而，最近我们取得了突破性进展，鉴定了两个血吸虫TGF2家族成员，TGF2同系物smenact和TGF2配体骨形态发生蛋白亚家族成员SmBMP。基于这些已发表的报道和我们的初步数据，我们假设TGF2信号通路在血吸虫中起两个不同的作用：1)在胚胎发生中，2)在表面被皮的维持中。为了解决这些假设，我们将：1)探索SmInAct在女性生殖潜能和胚胎发生中的作用；2)探索TGF2配体在血吸虫被膜生物学中的作用；3)探索TGF2配体的表达调控。通过在血吸虫中抑制内源基因表达和表达转基因的技术的发展，我们解决这些问题的能力得到了极大的提高，我们打算在本提案中充分利用这些技术。我们相信，我们的建议解决了血吸虫生物学的新领域，并有可能确定化疗的新靶点。这一点很重要，因为我们目前只能广泛获得一种治疗血吸虫病的药物吡喹酮，因此必须认为对这种药物产生耐药性的可能性很高。

DESCRIPTION (provided by applicant): Schistosomiasis, a disease that afflicts 200 million people, is caused by helminth parasites of the genus Schistosoma. Schistosomes are complex metazoan pathogens that belong to an early diverging branch of the Bilateria, the Lophotrochozoans. Little is known of the molecular basis of cell to cell communication in animals in this group, but targeted studies and genome sequencing efforts have revealed that, not surprisingly, schistosomes contain some of the intercellular signaling systems that are found in higher order metazoa. Amongst these, we are particularly interested in the transforming growth factor 2 (TGF2) pathways. Elucidating the role(s) of this pathway in schistosome biology will be the goal of this proposal. Central to our view of what the TGF2 pathway might be doing in schistosomes has been our failure to identify a gene for a TGF2 ligand in these organisms, which led us to hypothesize that the TGF2 signaling pathway in schistosomes evolved to receive signals from host TGF2 ligands, a concept that was given credence by findings that schistosome TGF2 receptors can respond to human TGF2 ligands. Recently however, we made a breakthrough by identifying two schistosome TGF2 family members, SmInAct, which is a TGF2 homologue, and SmBMP, a member of the Bone Morphogenetic Protein subfamily of TGF2 ligands. Based on these published reports and our preliminary data we hypothesize that the TGF2 signaling pathway plays two distinct roles in schistosomes: 1) in embryogenesis, and 2) in the maintenance of the surface tegument. To address these hypotheses we will: 1) Explore the role of SmInAct in female reproductive potential and in embryogenesis; 2) Explore the role of TGF2 ligands in schistosome tegument biology, and 3) Explore the regulation of expression of TGF2 ligands. Our ability to address these issues has improved dramatically recently through the development of techniques for inhibiting endogenous gene expression and expressing transgenes in schistosomes, and we intend to make full use of these technologies in this proposal. We believe that our proposal addresses new and novel areas of schistosome biology and has the potential to identify new targets for chemotherapy. This is important since we currently have broad access to only one drug, praziquantel, for the treatment of schistosomiasis and consequently the potential for the development of resistance to this drug must be considered high.