Autophagy and ocular toxoplasmosis.

自噬和眼弓形体病。

• 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
• 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

 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（由申请人提供）：专性细胞内原生动物刚地弓形虫是世界上感染性视网膜脉络膜炎最常见的病因。眼弓形虫病是导致视力丧失的重要原因，特别是在先天性 感染以及老年人和免疫抑制者。不幸的是，目前的治疗方案并不理想，因为没有证据表明它们可以改善视觉功能或预防疾病复发。更好地了解促进眼弓形虫病的机制有可能导致新的和改进的治疗方法对这种疾病。T.弓形虫在宿主细胞内以寄生虫泡的形式存在，该寄生虫泡不能与溶酶体融合，以便寄生虫能够存活和复制。自噬是溶酶体降解的组成性过程。最近的研究发现了一种新的病原体生存模式，即T。弓形虫激活宿主细胞中的EGFR信号传导，从而避免自噬降解。这一发现可能与眼弓形虫病有关，因为自噬蛋白缺陷的小鼠对眼弓形虫病的易感性增强。本申请的目的是了解T.弓形虫激活视网膜细胞中的EGFR信号传导，并确定EGFR信号传导在眼弓形虫病发展中的作用。这项研究的中心假设是T.弓形虫通过激活特异性宿主细胞蛋白激酶引起EGFR信号传导延长，抑制EGFR信号传导增强对眼弓形虫病的保护。这一假设将使用阻断特定信号通路的遗传方法、免疫化学研究和转基因小鼠进行测试。在第一个具体目标中，我们将确定蛋白激酶的激活是否导致T细胞中EGFR激活延长。感染了刚第虫的视网膜细胞在第二个目标中，我们将确定细胞类型特异性EGFR阻断是否增强对眼部弓形虫病的抵抗力。在第三个目标中，我们将确定EGFR的抑制如何保护眼弓形虫病。这项工作可能会导致新的战略，以消除T。并基于调节宿主细胞信号传导治疗眼弓形虫病。