Cardiac Cell Entry-Inhibition and Protection Therapy for Chronic Chagas Disease

描述(申请人提供)：专性细胞内原生动物克氏锥虫引起恰加斯病，这是拉丁美洲发病率和死亡率的主要原因。在拉丁美洲和美国等发达国家，这是一个主要的经济负担，主要是由于大约30%的查格斯病患者进展为慢性查加斯心肌病。慢性查加斯心脏病的特点是全身局限性炎症、纤维化、心律失常、充血性心力衰竭和猝死。目前还没有能够改善慢性查加斯心肌病的药物。心脏移植是唯一的治疗方法，但由于保护心脏的困难，这是不现实的。这项建议的目的是确定一种新的先导化合物的最佳剂量和动力学方案，与初步结果一致，有效地阻断T CRUZI进入心肌细胞和心脏成纤维细胞，逆转慢性Chagas心肌病小鼠模型的心脏寄生虫、炎症和纤维化。这种新型抗锥虫化合物的基本概念与抗病毒药物马拉韦罗相似，马拉韦罗通过阻止艾滋病毒进入CD4淋巴细胞来发挥作用。马拉韦罗目前用于治疗艾滋病。我们建议确定1)最佳地减少慢性心肌病小鼠心脏寄生虫的生物进入细胞抑制剂的剂量方案；2)仿效生物的合成肽的剂量方案，最佳地降低慢性心肌病小鼠的心脏寄生率；3)交换先导抗锥虫化合物中的多肽基序是否提高治疗效率；以及4)合成肽与心肌细胞上的进入受体在刺激过程中的不同相互作用的机制。 要么是宿主细胞入侵，要么是提高治疗效率的营养反应。该项目将使用生化、寄生虫学、遗传学、细胞化学和非侵入性诊断方法，并突出了解控制细胞内微生物进入其栖息地的分子机制的翻译价值。

DESCRIPTION (provided by applicant): The obligate intracellular protozoan Trypanosoma cruzi causes Chagas' disease, a leading cause of morbidity and mortality in Latin America. It is a major economic burden in Latin America and in developed counties such as the USA, largely due to the approximately 30% of chagasic patients who progress to chronic Chagas cardiomyopathy. Chronic Chagas heart disease is characterized by generalized focal inflammation, fibrosis, arrhythmias, congestive heart failure and sudden death. There are no drugs capable of ameliorating chronic Chagas cardiomyopathy. Heart transplant is the only cure but it is not practical due to the difficulty is securing hearts. The goal of this proposal is to determine the optimal dose and kinetic regimen of a novel lead compound that, in accord with preliminary results, effectively block T cruzi entry into cardiomyocytes and cardiac fibroblasts, reversing cardiac parasitism, inflammation and fibrosis in a mouse model of chronic Chagas cardiomyopathy. The concept underlying the novel antitrypanosomal compound is similar to that antiviral Maraviroc, which works by blocking HIV entry into CD4 lymphocytes. Maraviroc is currently used to treat AIDS. We propose to determine 1) dose regimen of biologic entry cell inhibitor that optimally reduces cardiac parasitism in mice with chronic cardiomyopathy; 2) dose regimen of a synthetic peptide modeled on the biologic, which optimally reduces cardiac parasitism in mice with chronic cardiomyopathy; 3) whether swapping peptide motifs in the lead antitrypanosomal compound improves therapeutic efficiency; and 4) mechanisms underlying differential interaction of synthetic peptides with entry receptors on cardiac cells in stimulating either host cell invasion or trophic response that improves therapeutic efficiency. The project wil use biochemical, parasitological, genetic, cytochemical and non-invasive diagnostic approaches and highlights the translational value of understanding molecular mechanisms governing entry of intracellular microbes into their habitat.