TGF-beta signaling in schistosomes

描述（由申请人提供）：血吸虫病是一种折磨2亿人的疾病，由血吸虫属的蠕虫寄生虫引起。血吸虫是复杂的后生动物病原体，属于双侧纲的早期分支分支，即Lophotrochozoans。在这组动物中，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，染色体含有一些在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（TGF-2）途径。阐明该途径在染色体生物学中的作用将是本提案的目标。我们对TGF 2通路可能在溶酶体中起作用的观点的核心是我们未能在这些生物体中鉴定TGF 2配体的基因，这使我们假设溶酶体中的TGF 2信号通路进化为接收来自宿主TGF 2配体的信号，这一概念通过发现溶酶体TGF 2受体可以对人TGF 2配体产生反应而得到证实。然而，最近，我们取得了突破，确定了两个共同体TGF 2家族成员，SmInAct，这是一个TGF 2同源物，和SmBMP，TGF 2配体的骨形态发生蛋白亚家族的成员。基于这些已发表的报告和我们的初步数据，我们假设TGF 2信号通路在胚胎小体中起两种不同的作用：1）在胚胎发生中，和2）在表面皮层的维持中。为了解决这些假设，我们将：1）探索SmInAct在女性生殖潜力和胚胎发生中的作用; 2）探索TGF 2配体在溶酶体被膜生物学中的作用; 3）探索TGF 2配体表达的调节。我们解决这些问题的能力已经大大提高，最近通过抑制内源性基因表达和表达转基因的技术的发展，我们打算充分利用这些技术在这个建议。我们相信，我们的建议解决了新的和新颖的领域的染色体生物学，并有可能确定新的目标化疗。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.