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

描述（由申请人提供）：专性细胞内原生动物克氏锥虫引起恰加斯病，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，主要原因是大约30%的恰加斯病患者发展为慢性恰加斯心肌病。慢性恰加斯心脏病的特点是全身性局灶性炎症、纤维化、心律失常、充血性心力衰竭和猝死。目前还没有药物能够改善慢性恰加斯心肌病。心脏移植是唯一的治疗方法，但由于很难获得心脏，因此不现实。本研究的目的是确定一种新型先导化合物的最佳剂量和动力学方案，该先导化合物与初步结果一致，可有效阻断T - cruzi进入心肌细胞和心脏成纤维细胞，逆转慢性恰加斯心肌病小鼠模型中的心脏寄生、炎症和纤维化。这种新型抗锥虫化合物的原理类似于抗病毒药物马拉维克，其作用原理是阻断HIV进入CD4淋巴细胞。马拉维克目前用于治疗艾滋病。我们建议确定1)生物进入细胞抑制剂的剂量方案，以最佳地减少慢性心肌病小鼠的心脏寄生；2)模拟生物合成肽对慢性心肌病小鼠心脏寄生影响的剂量方案；3)交换抗锥虫体先导化合物中的肽基序是否能提高治疗效率；4)合成肽与心肌细胞进入受体的差异相互作用机制

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.