EGF FAMILY OF GROWTH FACTORS IN CHAGAS' DISEASE

查加斯病是由克氏锥虫引起的，在从美国南部到阿根廷的拉丁美洲许多地区是发病率和死亡率的主要原因。在高达10%-40%的感染者中，心脏将受到损害，在疾病流行的地区因心力衰竭而死亡。虽然在美国并不常见，但估计有100,000多名感染者居住在这个国家，有迹象表明，在那里遇到的病例将会越来越多。恰加斯病的几乎所有方面的发病机制仍然是我们所不知道的。了解哺乳动物寄主体内寄生虫增殖的分子机制可以为制定控制克氏毛滴虫感染的策略提供依据。我们实验室最近的研究表明，表皮生长因子(EGF)、转化生长因子α(TGF-α)和肝素结合EGF(HB-EGF)可以特异性和选择性地与克鲁兹毛滴虫的无鞭毛体结合，诱导宿主细胞内外的生长，并且哺乳动物EGF受体的两个单抗可以与克鲁兹毛滴虫的一种独特的表面蛋白相互作用。这项建议的长期目标是了解这些与EGF受体结合的生长因子调节哺乳动物宿主细胞中克氏锥虫生长的机制。这项建议的具体目标是开始阐明这些生长因子在无鞭毛体上诱导的信号转导途径。为此，我们建议a)研究配体与寄生虫表面受体结合后发生的信号转导事件的诱导；b)研究配基与寄生虫表面受体结合后EGF受体在克氏锥虫无鞭毛虫中的内化和下调；b)研究配基结合后克氏锥虫无鞭毛虫中EGF结合的内化和下调；c)研究其他与EGF受体结合的生长因子与无鞭毛虫受体结合的能力及其在实验性克氏锥虫感染中的生物学相关性；d)在感染克氏锥虫的细胞中跟踪EGF受体的内化途径。这些研究有可能阐明克鲁兹毛滴虫利用宿主细胞正常可用的途径在细胞内建立的新机制。无鞭毛体具有生长因子受体同源物的事实为理解细胞内病原体的生长调节提供了一个独特的模型。从长远来看，对这种新机制的识别将导致开发控制克氏毛滴虫感染和其他传染病的分子手段。

Chagas' disease is caused by Trypanosoma cruzi and is a major cause of morbidity and mortality in many areas of Latin American ranging from the Southern United States to Argentina. In up to 10-40% of those infected the heart will be compromised leading to death by heart failure in areas where the disease is endemic. Although not common the United States there are estimated to be more than 100,000 infected persons residing in this country where it has been suggested that cases will be encountered in increasing numbers. The pathogenesis of virtually all aspects of Chagas' disease continues to elude our knowledge. An understanding of the molecular mechanisms involved in parasite proliferation in the mammalian host could provide the basis for developing strategies to control T. cruzi infection. Recent studies from our laboratory have shown that epidermal growth factor (EGF), Transforming growth factor a (TGF-alpha) and Heparin Binding EGF (HB-EGF) bind specifically and selectively to the amastigote form of T. cruzi to induce growth within and outside host cells and that two monoclonal antibodies to the mammalian EGF receptor interact with a distinct surface protein of T. cruzi. The long term objective of this proposal is to understand the mechanisms by which these growth factors that bind to the EGF receptor modulate T. cruzi growth in mammalian host cells. The specific goal of this proposal is to begin to elucidate the signal transduction pathways induced by these growth factors on amastigotes. To this end we propose a) to study the induction of signal transduction events that occur after ligand binding to its receptor on the parasite surface; b) to study the internalization and down regulation of the EGF receptor in T. cruzi amastigotes following ligand binding to its receptor on the parasite surface; b) to study the internalization and down regulation of the EGF binding in T. cruzi amastigotes following ligand binding; c) to study the ability of other growth factors that bind to the EGF receptor to bind to the amastigote receptor and their biological relevance in experimental T. cruzi infections; d) to follow the internalization pathways of EGF receptor in a T. cruzi infected cell. These studies have the potential to elucidate novel mechanisms by which T. cruzi exploits pathways normally available to host cells to establish intracellularly. The fact that amastigotes have a growth factor receptor homologue provides a unique model to understand growth regulation of intracellular human pathogens. In the long run, identification of such novel mechanisms would lead to developing molecular means to control T. cruzi infection and other infectious diseases.