Autophagy and ocular toxoplasmosis.

自噬和眼弓形体病。

基本信息

批准号：
8884281
负责人：
CARLOS S SUBAUSTE
金额：
$ 35.66万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884281
关键词：
Affect Autophagocytosis Autophagosome Bacterial Adhesins Biological Blindness Blood Cells Child Chorioretinitis Development Disease Disease Progression Dominant-Negative Mutation EGF-Like Domain Elderly Endothelial Cells Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Immune Immunocompetent Immunodeficient Mouse Infection Lead Ligands Lysosomes Mediating Microglia Mus Nature Ocular Toxoplasmosis Outcome Parasites Population Predisposition Process Protein Inhibition Protein Kinase Proteins Receptor Activation Receptor Signaling Recurrent disease Research Resistance Retina Retinal Retinitis Role Route Signal Pathway Signal Transduction Structure of retinal pigment epithelium T-Lymphocyte TNFRSF5 gene Testing Therapeutic Time Toxoplasma gondii Transactivation Transgenic Mice Translating Up-Regulation Vacuole Vision Visual Visual Acuity Work base cell type congenital infection design genetic approach immune activation immunosuppressed improved in vivo killings macrophage new therapeutic target novel parasite invasion pathogen prevent public health relevance research study resistance mechanism

项目摘要

DESCRIPTION (provided by applicant): The obligate intracellular protozoan Toxoplasma gondii is the most common cause of infectious retinochoroiditis in the world. Ocular toxoplasmosis is an important cause of loss of visual acuity especially in children with congenital infection as well as the elderly and the immunosuppressed. Unfortunately, current treatment options are not ideal since there is no evidence that they improve visual function or prevent relapses of the disease. A better understanding of the mechanisms that promote ocular toxoplasmosis has the potential to lead to new and improved therapeutic approaches against this disease. T. gondii resides within host cells in a parasitophorous vacuole that must not fuse with lysosomes so that the parasite can survive and replicate. Autophagy is a constitutive process of lysosomal degradation. Recent studies identified a new paradigm of pathogen survival whereby T. gondii activates EGFR signaling in host cells and as a result avoids autophagic degradation. This finding is likely relevant to ocular toxoplasmosis because mice deficient in autophagy proteins have enhanced susceptibility to ocular toxoplasmosis. The objectives of this application are to understand how T. gondii activates EGFR signaling in retinal cells and to determine the role of EGFR signaling in the development of ocular toxoplasmosis. The central hypothesis for the proposed research is that T. gondii causes prolonged EGFR signaling by activating a specific host cell protein kinase and inhibition of EGFR signaling enhances protection against ocular toxoplasmosis. This hypothesis will be tested using genetic approaches that block specific signaling pathways, immunochemical studies and transgenic mice. In the first specific aim we will determine if activation of a protein kinase causes prolonge EGFR activation in T. gondii-infected retinal cells. In the second aim, we will determine if cell type-specific blockade of EGFR enhances resistance to ocular toxoplasmosis. In the third aim, we will determine how inhibition of EGFR protects against ocular toxoplasmosis. The proposed work may lead to new strategies to eradicate T. gondii and treat ocular toxoplasmosis based on modulation host cell signaling.

描述（由适用提供）：专性细胞内原生动物毒素弓形虫是世界上传染性视网膜炎的最常见原因。眼癌是视力丧失的重要原因，尤其是先天儿童感染以及古老的和免疫抑制。不幸的是，目前的治疗选择不是理想的选择，因为没有证据表明它们可以改善视觉功能或防止疾病的继电器。更好地了解促进眼毒的机制有可能导致针对该疾病的新的和改善的治疗方法。寄生虫吸尘器中宿主细胞内的巨型gondii住宅必须与溶酶体融合，以使寄生虫能够生存并复制。自噬是溶酶体降解的组成过程。最近的研究确定了一种新的病原体生存范式，从而在gondii中激活宿主细胞中的EGFR信号传导，因此避免了自噬降解。这一发现可能与眼部弓形虫病有关，因为缺乏自噬蛋白质的小鼠对眼部毒素的敏感性增强了。该应用的目标是了解弓形虫如何激活视网膜细胞中的EGFR信号传导，并确定EGFR信号传导在眼部弓形虫病发展中的作用。拟议研究的中心假设是，弓形虫通过激活特定的宿主细胞蛋白激酶和抑制EGFR信号增强对眼癌的保护，从而导致EGFR信号传导延长。该假设将使用阻断特定信号通路，免疫化学研究和转基因小鼠的遗传方法进行检验。在第一个特定目的中，我们将确定蛋白激酶的激活是否引起gondii感染的视网膜细胞中的prolonge EGFR激活。在第二个目标中，我们将确定EGFR的细胞类型特异性阻断是否增强了对眼癌的耐药性。在第三个目标中，我们将确定抑制EGFR如何预防眼毒。拟议的工作可能导致基于调制宿主细胞信号传导的新策略，以消除T. gondii并治疗眼部弓形虫病。