A Genetic Model of Uveitis

葡萄膜炎的遗传模型

• 批准号: 6928455
• 负责人: TAMMY M MARTIN
• 金额: $ 15.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928455
• 关键词: disease /disorder model; flow cytometry; gene expression; genetic disorder; genetic models; genetic regulation; genetically modified animals; immunocytochemistry; inflammation; intermolecular interaction; laboratory mouse; model design /development; molecular pathology; newborn animals; peptidoglycan; polymerase chain reaction; protein localization; protein structure function; recombinant DNA; transport proteins; uveitis

DESCRIPTION (provided by applicant): Uveitis research is poised to benefit from the discipline of genetics. Recently, mutations in a gene known as NOD2 (or CARD15) have been found to cause Blau syndrome (also called Jabs disease or familial juvenile systemic granulomatosis), a rare form of uveal, skin and joint granulomatous inflammation. Blau syndrome is inherited in an autosomal dominant pattern, and the discovery that a single amino acid change in the NOD2 protein can result in uveitis provides an incredible research opportunity. The NOD2 gene product can participate in inflammatory responses by activating NFkappaB in response to the bacterial peptidoglycan subunit, muramyl dipeptide. NOD2 also contains a protein domain that may allow participation in apoptotic cellular pathways. The exact mechanisms by which NOD2 may be involved in initiating, prolonging or regulating immune responses relating to ocular inflammation is unknown. In an effort to produce a genetic model of uveitis, and to study the basic biology of NOD2 as it relates to ocular inflammatory responses, this is a proposal to create transgenic mice expressing the wild-type NOD2 cDNA and expressing a representative Blau syndrome NOD2 mutation. The specific aims are as follows: 1. To determine the expression pattern of NOD2 in the normal mouse. This will be accomplished by creating a mouse expressing a bicistronic murine NOD2 and yellow fluorescent protein transgene. Expression in several tissues will be examined, with particular attention paid to ocular tissues. Both normal and inflamed eyes will be studied. 2. To examine whether over-expression of NOD2 alters susceptibility to muramyl dipeptide-induced uveitis. Since NOD2 appears to regulate the intracellular response to muramyl dipeptide and because muramyl dipeptide is a known trigger of uveitis, the hypothesis that over-expression of NOD2 increases intensity of uveitis in a murine model will be tested. 3. To test the hypothesis that expression of NOD2 with a Blau syndrome mutation results in a model of spontaneous uveitis. Both transgenic mice and transgenic mice crossed with NOD2 knock-out mice will be studied.

描述（由申请人提供）：葡萄膜炎研究有望从遗传学学科中受益。最近，发现一种称为NOD2（或CARD15）的基因中的突变引起Blau综合征（也称为JABS疾病或家族性少年全身性肉芽肿），这是一种罕见的卵巢，皮肤和关节肉芽肿性炎症。 BLAU综合征是以常染色体显性遗传模式遗传的，发现NOD2蛋白中的单个氨基酸变化可以导致葡萄膜炎提供了令人难以置信的研究机会。 NOD2基因产物可以通过激活NFKAPPAB来响应细菌肽聚糖亚基Muramyl二肽来参与炎症反应。 NOD2还包含一个蛋白质结构域，该结构域可能允许参与凋亡的细胞途径。 NOD2可能参与引发，延长或调节与眼部炎症的免疫反应的确切机制尚不清楚。 为了产生葡萄膜炎的遗传模型，并研究了NOD2的基本生物学，因为它与眼部炎症反应有关，这是创建表达野生型NOD2 cDNA并表达代表性BLAU综合综合征NOD2突变的转基因小鼠的建议。具体目的如下： 1。确定正常小鼠中NOD2的表达模式。这将通过创建表达双菌鼠NOD2和黄色荧光蛋白转基因的小鼠来实现。将检查几个组织中的表达，并特别注意眼组织。将研究正常和发炎的眼睛。 2。检查NOD2的过表达是否会改变对穆拉米基二肽诱导的葡萄膜炎的敏感性。 由于NOD2似乎调节了对穆拉米尔二肽的细胞内反应，并且由于穆拉米基二肽是葡萄膜炎的已知触发因素，因此将测试NOD2的过表达在鼠模型中增加葡萄膜炎的强度。 3。检验以下假设：NOD2用BLAU综合征突变的表达导致自发葡萄膜炎的模型。将研究与NOD2敲除小鼠交叉的转基因小鼠和转基因小鼠。