TGF-beta signaling in schistosomes

描述(申请人提供)：血吸虫病是一种由血吸虫属寄生虫引起的疾病，困扰着2亿人。血吸虫是一种复杂的后生动物病原体，属于双毛虫的一个早期发散分支，即线虫。对这一群体中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，不出所料，血吸虫包含一些在更高级后生动物中发现的细胞间信号系统。其中，我们特别感兴趣的是转化生长因子2(TGF2)途径。阐明这一途径在血吸虫生物学中的作用(S)将是这项提议的目标。我们对TGF2通路在血吸虫中可能起什么作用的核心观点是，我们未能在这些生物体中确定TGF2配体的基因，这导致我们假设血吸虫中的TGF2信号通路进化为接收宿主TGF2配体的信号，这一发现证实了血吸虫TGF2受体可以与人TGF2配体反应的发现。然而，最近我们取得了突破，鉴定了两个血吸虫TGF2家族成员，SmInAct和SmBMP，SmInAct是TGF2的同源物，SmBMP是TGF2配体的骨形态发生蛋白亚家族的成员。根据这些已发表的报道和我们的初步数据，我们推测TGF2信号通路在血吸虫中发挥两个不同的作用：1)在胚胎发育中，2)在表面被层的维持中。为了解决这些假说，我们将：1)探索SmInAct在女性生殖潜能和胚胎发育中的作用；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。最近，通过开发抑制血吸虫内源性基因表达和表达转基因的技术，我们解决这些问题的能力已经显著提高，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，并有可能确定新的化疗靶点。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抗药性的可能性很高。

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.