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Autophagy and ocular toxoplasmosis.

自噬和眼弓形体病。

基本信息

批准号：
9235430
负责人：
CARLOS S SUBAUSTE
金额：
$ 6.3万
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/9235430
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 Health 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 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.