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

慢性恰加斯病的心肌细胞进入抑制和保护疗法

• 批准号: 8762850
• 负责人: Mercio A Perrin
• 金额: $ 44.15万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762850
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Acute Disease; Affinity; Americas; Amino Acid Sequence; Anti-HIV Agents; Antibodies; Antiviral Agents; Area; Arrhythmia; Attenuated; Back; Benznidazole; Binding; Biochemical; Boxing; CD4 Positive T Lymphocytes; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Chagas Cardiomyopathy; Chagas Disease; Chronic; Clinical; Communicable Diseases; Congestive Heart Failure; County; Custom; Deuterium; Developed Countries; Diagnostic; Dose; Echocardiography; Economic Burden; Economics; Ensure; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Fibrosis; Genetic; Genetic Engineering; Goals; HIV; Habitats; Heart; Heart Diseases; Heart Transplantation; Heart failure; Histocytochemistry; Histology; Immunofluorescence Immunologic; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Injection of therapeutic agent; Invaded; Kinetics; Latin America; Lead; Mass Spectrum Analysis; Medical center; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; Names; Neurotrophic Tyrosine Kinase Receptor Type 1; Neurotrophic Tyrosine Kinase Receptor Type 3; Nifurtimox; Oxidative Stress; Parasites; Pathologist; Patients; Peptides; Pharmaceutical Preparations; Positioning Attribute; Protein Engineering; Regimen; Research; Scientist; Secure; Signal Transduction; Site; Structural Biologist; Structure; Sudden Death; Surface Plasmon Resonance; Technology; Therapeutic; Trypanocidal Agents; Trypanosoma cruzi; United States; Work; base; chemokine receptor; clinical application; cost; cytokine; design; improved; inhibitor/antagonist; innovation; mimicry; mortality; mouse model; mutant; neurotrophic factor; novel; novel strategies; obligate intracellular parasite; parasitism; prevent; public health relevance; receptor; receptor binding; research study; response; stem; success; synthetic peptide

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.

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，这是拉丁美洲发病和死亡的主要原因。它是拉丁美洲和美国等发达国家的主要经济负担，主要原因是大约 30% 的恰加斯病患者进展为慢性恰加斯心肌病。慢性恰加斯心脏病的特征是全身局灶性炎症、纤维化、心律失常、充血性心力衰竭和猝死。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，但由于难以保护心脏，因此不切实际。该提案的目标是确定一种新型先导化合物的最佳剂量和动力学方案，根据初步结果，该化合物可有效阻止克氏锥虫进入心肌细胞和心脏成纤维细胞，逆转慢性查加斯心肌病小鼠模型的心脏寄生、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 Maraviroc 类似，后者的作用是阻止 HIV 进入 CD4 淋巴细胞。 Maraviroc 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，以最佳地减少患有慢性心肌病的小鼠的心脏寄生； 2) 以生物制剂为模型的合成肽的剂量方案，可最佳地减少患有慢性心肌病的小鼠的心脏寄生； 3) 交换先导抗锥虫化合物中的肽基序是否可以提高治疗效率； 4) 合成肽与心肌细胞上的进入受体在刺激过程中差异相互作用的机制 宿主细胞入侵或营养反应可提高治疗效率。该项目将使用生物化学、寄生虫学、遗传学、细胞化学和非侵入性诊断方法，并强调了解控制细胞内微生物进入其栖息地的分子机制的转化价值。