Growth factor mimicry in Trypanosoma cruzi invasion of the heart

描述(申请人提供)：查加斯病，由专性细胞内原生动物锥虫克氏锥虫引起，是拉丁美洲最重要的寄生虫病，困扰着800多万人，其中30%-40%的人在急性疾病期间寄生虫首次入侵心肌细胞数年或数十年后患有或将发展为心肌病。这项建议的目的是破译克氏毛滴虫入侵心肌细胞的分子基础，并深入了解在急性疾病期间保护心脏的共生宿主和寄生虫的相互作用。 和无症状的不确定阶段，尽管有持续的寄生。初步研究表明，克氏锥虫使用其表面配体PDNF与心肌细胞受体酪氨酸激酶TrkC结合，从而导致细胞侵袭。此外，克鲁兹毛滴虫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，神经生长因子是心脏神经和其他组织中已被证实的修复和损伤逆转触发因素，提示了一种有助于控制感染克鲁兹毛滴虫的心脏损伤的机制。最后，PDNF中的asp-box基序似乎不同地参与了寄生虫入侵和营养刺激。 宿主细胞。通过这些观察，我们建议确定T.ruzi是否以及如何通过PDNF，1)利用神经营养素受体TrkC入侵心肌细胞；2)通过心肌细胞分泌的NGF促进旁分泌信号来保护心脏神经免受损伤；3)通过Asp盒与Trk受体不同地相互作用，刺激宿主细胞侵袭或营养反应。这些研究将使用分子生物学和生化方法、免疫分析、细胞培养和动物模型来实现特定的目标。此外，该项目可能导致开发新的、定制设计的、基于PDNF的疗法，以选择性地减少心脏和其他富含Trk的器官中的T.ruzi负担，并通过促进NGF的产生，逆转因NGF缺乏而导致的恶化的心脏神经。

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.