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

基本信息

批准号：
8846540
负责人：
Mercio A Perrin
金额：
$ 45.78万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
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/8846540
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 Health 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 receptor receptor binding research study response stem success synthetic peptide

项目摘要

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）：Cruzi的专性细胞内原生动物锥虫引起了Chagas疾病，这是拉丁美洲发病率和死亡率的主要原因。这是拉丁美洲和美国等发达县的主要经济负担，这主要是由于大约30％的chagasic患者发展为慢性chagas心肌病。慢性Chagas心脏病的特征是普遍的局灶性炎症，纤维化，心律不齐，充血性心力衰竭和猝死。没有能够改善慢性Chagas心肌病的药物。心脏移植是唯一的治疗方法，但由于困难是确保心脏的困难，这是不切实际的。该提案的目的是确定一种新型铅化合物的最佳剂量和动力学方案，该铅化合物有效地阻止了T Cruzi进入心肌细胞和心脏成纤维细胞，逆转心脏寄生虫，从而使心脏寄生虫和纤维化在慢性Chagas Cardiomyopathy的小鼠模型中。新型抗胰腺体化合物的基础概念与抗病毒maraviroc相似，该抗病毒药是通过阻止HIV进入CD4淋巴细胞的作用。 Maraviroc目前用于治疗艾滋病。我们建议确定1）生物入口细胞抑制剂的剂量方案，可最佳地降低患有慢性心肌病小鼠的心脏寄生虫； 2）在生物学上建模的合成肽的剂量方案，该肽可以最佳地降低患有慢性心肌病小鼠的心脏寄生虫； 3）在铅抗丙糖体化合物中交换肽基序是否可以提高治疗效率； 4）合成肽与入口受体在刺激中的差异相互作用的机制宿主细胞侵袭或营养反应可提高治疗效率。该项目将使用生化，寄生学，遗传学，细胞化学和非侵入性诊断方法，并突出了了解将细胞内微生物进入其栖息地的分子机制的转化价值。