TGF-beta signaling in schistosomes

血吸虫病是一种折磨2亿人的疾病， 血吸虫血吸虫是复杂的后生动物病原体，属于血吸虫的早期分支分支， 双体动物，即裂轮动物。对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， 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，我们对转化生长因子β（TGF β）途径特别感兴趣。阐明该途径在染色体生物学中的作用将是本提案的目标。我们关于TGF β通路在染色体中可能起作用的观点的核心是我们未能在这些生物体中鉴定TGF β配体的基因，这导致我们假设染色体中的TGF β信号通路进化为从宿主TGF β配体接收信号，这一概念通过发现染色体TGF β受体可以对人类TGF β配体产生反应而得到证实。然而，最近，我们通过鉴定两种TGF β家族成员SmInAct和SmBMP取得了突破性进展，SmInAct是TGF β同源物，SmBMP是TGF β的成员。 TGF β配体的骨形态发生蛋白亚家族。基于这些已发表的报告和我们的初步数据，我们假设TGF β信号通路在染色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)探讨SmInAct在雌性生殖潜能和胚胎发育中的作用; 2）探讨SmInAct在雌性生殖潜能和胚胎发育中的作用。 TGF β配体在溶酶体被膜生物学中的作用; 3）探讨TGF β配体的表达调控。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。

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 beta (TGF beta) 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 TGF beta pathway might be doing in schistosomes has been our failure to identify a gene for a TGF beta ligand in these organisms, which led us to hypothesize that the TGF beta signaling pathway in schistosomes evolved to receive signals from host TGF beta ligands, a concept that was given credence by findings that schistosome TGF beta receptors can respond to human TGF beta ligands. Recently however, we made a breakthrough by identifying two schistosome TGF beta family members, SmInAct, which is a TGF beta homologue, and SmBMP, a member of the Bone Morphogenetic Protein subfamily of TGF beta ligands. Based on these published reports and our preliminary data we hypothesize that the TGF beta 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 TGF beta ligands in schistosome tegument biology, and 3) Explore the regulation of expression of TGF beta 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.