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）：由克鲁兹的专有细胞内原生动物锥虫瘤引起的Chagas疾病，是拉丁美洲最重要的寄生虫病，遭受了超过800万人，其中30-40％，其中30-40％的人患有或将在寄生虫病年或十年后首次侵袭心脏瘤性心脏瘤性疾病。该提案的目的是破译t. cruzi入侵心肌细胞的分子基础，并深入了解共生宿主 - 寄生虫相互作用，这些相互作用在急性疾病期间保护心脏尽管持续存在寄生虫，但无症状的不确定阶段。初步研究表明，克鲁兹（T. cruzi）使用其表面配体PDNF结合心肌细胞受体酪氨酸激酶TRKC，导致细胞侵袭。此外，Cruzi T. cruzi的识别和激活心肌细胞-TRKC诱导神经生长因子（NGF）的表达和分泌，这是心脏和其他组织神经的可靠修复和损伤逆转触发因素，这表明了一种机制，有助于在T. Cruzi感染的心脏中损害控制。最后，PDNF中的ASP-box基序似乎与寄生虫侵袭和营养刺激有关宿主细胞。追求这些观察结果，我们建议确定Cruzi是否以及如何通过PDNF，1）利用神经营养蛋白受体TRKC入侵心肌细胞； 2）促进旁分泌信号传导槽心肌细胞分泌的NGF，以保护心脏神经免受损伤； 3）通过ASP盒与TRK受体差异相互作用，以刺激宿主细胞Invasio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的。此外，该项目可能导致新型，定制设计的基于PDNF的治疗剂的发展，以选择性地减轻心脏和其他富含TRK的器官的T. cruzi负担，并通过增强NGF的产生，从而促进NGF缺乏症的反向恶化。