Growth factor mimicry in Trypanosoma cruzi invasion of the heart

克氏锥虫入侵心脏的生长因子拟态

基本信息

批准号：
8664186
负责人：
Mercio A Perrin
金额：
$ 38.78万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-06 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664186
关键词：
Acute Acute Disease Adhesions Americas Amino Acid Sequence Amino Acids Animal Model Autocrine Communication Binding Binding Sites Biochemical Biological Boxing Caliber Cardiac Cardiac Myocytes Cardiomyopathies Cell Culture Techniques Cell surface Cells Chagas Disease Chronic Custom Dendrites Development Diabetic Neuropathies Disease Engineering Goals Growth Factor Habitats Heart Heart Diseases Huntington Disease Immunoassay Infection Injury Invaded Latin America Lead Ligands Light Mediating Membrane Methods Molecular Molecular Biology Morbidity - disease rate Mus NGFR Protein Nerve Nerve Growth Factor Receptors Nerve Growth Factors Neurons Neurotrophic Tyrosine Kinase Receptor Type 3 Organ Paracrine Communication Parasites Parasitic Diseases Patients Phase Production Publishing Receptor Protein-Tyrosine Kinases Recombinants Reporting Research Role Signal Transduction Structure Surface Testing Therapeutic Therapeutic Uses Tissues Transcript Trypanosoma cruzi autocrine base design diabetic drug development heart innervation injury and repair insight mimicry mortality mutant neurotrophic factor novel paracrine parasite invasion parasitism receptor response

项目摘要

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.

描述（由申请人提供）：恰加斯病是由专性细胞内原生动物克氏锥虫引起的，是拉丁美洲最重要的寄生虫病，困扰着超过 800 万人，其中 30-40% 的人患有或将患上心肌病。寄生虫在急性疾病期间首次侵入心肌细胞数十年后。该提案的目标是破译克氏锥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-寄生虫相互作用以及无症状的不确定期，尽管有持续的寄生。初步研究表明，克氏锥虫利用其表面配体PDNF结合心肌细胞受体酪氨酸激酶TrkC，导致细胞侵袭。此外，克氏锥虫对心肌细胞 TrkC 的识别和激活会诱导神经生长因子 (NGF) 的表达和分泌，神经生长因子 (NGF) 是心脏和其他组织神经修复和损伤逆转的触发因素，这表明一种有助于控制损伤的机制。克鲁兹锥虫感染的心脏。最后，PDNF 中的 Asp-box 基序似乎不同程度地参与了寄生虫入侵和营养刺激。宿主细胞。根据这些观察结果，我们建议确定克氏锥虫是否以及如何通过 PDNF，1) 利用神经营养蛋白受体 TrkC 侵入心肌细胞； 2）通过心肌细胞分泌的NGF促进旁分泌信号传导，保护心脏神经免受损伤； 3) 通过 Asp-box 与 Trk 受体发生差异性相互作用，刺激宿主细胞侵袭或营养反应。这些研究将采用分子生物学和生化方法、免疫测定、细胞培养和动物模型来实现特定目标。此外，该项目可能会导致新型、定制设计、基于PDNF的疗法的开发，以选择性地减少心脏和其他富含Trk的器官中的克氏锥虫负担，并通过促进NGF的产生，逆转导致恶化的心脏神经支配。来自 NGF 缺乏。