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

• 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
• 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

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）：恰加斯病由专性细胞内原生动物克氏锥虫引起，是拉丁美洲最重要的寄生虫病，影响着超过 800 万人，其中 30-40% 的人在寄生虫在急性疾病期间首次侵入心肌细胞数年或数十年后患有或将患上心肌病。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 and the asymptomatic indeterminate phase, despite persistent parasitism.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，这表明一种有助于克氏锥虫感染的心脏损伤控制的机制。 Lastly, Asp-box motifs in PDNF appear to be involved differentially in parasite invasion and trophic stimulation of 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) 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.此外，该项目可能会导致开发新型、定制的、基于 PDNF 的疗法，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，逆转因 NGF 缺乏而导致的恶化的心脏神经支配。