Growth factor mimicry in Trypanosoma cruzi invasion of the heart

描述（由申请人提供）：恰加斯病由专性细胞内原生动物克氏锥虫引起，是拉丁美洲最重要的寄生虫病，影响超过800万人，其中30-40%在急性疾病期间寄生虫首次侵入心肌细胞数年或数十年后患有或将发展为心肌病。这项计划的目标是破译T. cruzi入侵心肌细胞，并深入了解在急性疾病期间保护心脏的共生宿主-寄生虫相互作用 和无症状的不确定阶段，尽管持续寄生。初步研究表明T. cruzi利用其表面配体PDNF结合心肌细胞受体酪氨酸激酶TrkC，导致细胞侵袭。此外，T. cruzi识别和激活心肌细胞-TrkC诱导神经生长因子（NGF）的表达和分泌，神经生长因子（NGF）是心脏和其他组织的神经中已证实的修复和损伤逆转触发因子，这表明有助于T.克鲁兹感染的心脏最后，PDNF中的Asp-box基序似乎与寄生虫入侵和对细胞的营养刺激有关。 宿主细胞追求这些意见，我们建议，以确定是否和如何T。cruzi通过PDNF，1）利用神经营养蛋白受体TrkC侵入心肌细胞; 2）通过心肌细胞分泌的NGF促进旁分泌信号传导以保护心脏神经免受损伤;和3）通过Asp-box与Trk受体差异性地相互作用以刺激宿主细胞侵入或营养应答。这些研究将采用分子生物学和生物化学方法、免疫测定、细胞培养和动物模型来实现特定目标。此外，该项目可能导致开发新的，定制设计的，基于PDNF的治疗方法，以选择性地减少T。通过增加心脏和其他富含Trk的器官中的cruzi负担，并通过促进NGF产生，逆转由NGF缺乏引起的心脏神经支配恶化。

DESCRIPTION (provided by applicant): Chagas' disease, caused by the obligate intracellular protozoan Trypanosoma cruzi, is the most important parasitic disease in Latin America, afflicting more than 8 million people, 30-40% of whom have or will develop cardiomyopathy years or decades after the parasite first invades cardiomyocytes during acute disease. The goal of this proposal is to decipher the molecular basis for T. cruzi invasion of cardiomyocytes and gain insight into the symbiotic host - parasite interactions that protect the heart during acute disease and the asymptomatic indeterminate phase, despite persistent parasitism. Preliminary studies suggest that T. cruzi uses its surface ligand PDNF to bind cardiomyocyte receptor tyrosine kinase TrkC, leading to cell invasion. Furthermore, T. cruzi recognition and activation of cardiomyocyte-TrkC induces expression and secretion of nerve growth factor (NGF), a proven repair and injury reversal trigger in nerves of the heart and other tissues, suggesting a mechanism that contributes to damage control in the T. cruzi-infected heart. Lastly, Asp-box motifs in PDNF appear to be involved differentially in parasite invasion and trophic stimulation of host cells. Pursuing these observations, we propose to determine whether and how T. cruzi, via PDNF, 1) exploits neurotrophin receptor TrkC to invade cardiomyocytes; 2) promotes paracrine signaling trough cardiomyocyte-secreted NGF to protect cardiac nerves against injury; and 3) differentially interacts with Trk receptors through Asp-boxes to stimulate either host cell invasio or trophic responses. These studies will employ molecular biology and biochemical methods, immunoassays, cell culture and animal models to achieve the specific aims. In addition, the project may lead to the development of novel, custom-designed, PDNF-based therapeutics to selectively reduce T. cruzi burden in the heart and other Trk-rich organs and, by boosting NGF production, reverse deteriorated heart innervation that results from NGF deficiency.