THE ROLE OF APOPTOTIC MOLECULES IN HERPETIC STROMAL

凋亡分子在疱疹间质中的作用

• 批准号: 7935224
• 负责人: Patrick M Stuart
• 金额: $ 34.44万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935224
• 关键词: Apoptosis; Apoptotic; Blindness; Cells; Cessation of life; Cicatrix; Communicable Diseases; Cornea; Corneal Diseases; Country; Data; Development; Disease; Eye; Eye diseases; Genes; Genome; Growth; Herpesvirus 1; Herpetic Keratitis; Human; Immune; Inbred BALB C Mice; Incidence; Infection; Inflammation; Inflammatory Response; Keratitis; Keratoplasty; Laboratories; Lead; Luciferases; Lymphoid Cell; Maintenance; Manuscripts; Mediating; Modeling; Monitor; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nervous system structure; Neurons; Peripheral; Play; Prevention; Publishing; Recurrence; Regulatory T-Lymphocyte; Reporting; Role; Simplexvirus; Structure of trigeminal ganglion; T-Lymphocyte; TNFRSF6 gene; Testing; Tissues; Tumor Necrosis Factor Ligand Superfamily Member 6; United States; Viral; Virus; Virus Diseases; Virus Latency; Virus Shedding; Wild Type Mouse; Work; cell type; corneal allograft; design; disease phenotype; irradiation; macrophage; mutant; neovascularization; neuropathology; neutrophil; ocular surface; prevent; public health relevance; success; trafficking

DESCRIPTION (provided by applicant): Our laboratory has been studying the role that Fas and Fas ligand play in corneal transplantation and have published several manuscripts detailing the importance of this interaction to the success of corneal allografts and the prevention of neovascularization of the cornea. However, the role that these apoptotic molecules play in herpetic eye disease remains to be fully delineated. The only report on this subject used a virus-mouse strain combination that does not produce significant disease. Thus the precise role that apoptotic molecules play in either causing or preventing HSV-1-mediated ocular disease is not clear. In order to bring more clarity to this situation, we performed preliminary studies wherein we infected BALB/c, and BALB-lpr (Fas mutants), and BALB-gld (Fas Ligand mutants) mice with the KOS strain of HSV-1 as well as C57BL/6 and its mutants with the McKrae strain of HSV-1, and monitored both corneal disease and shedding of virus from the ocular surface. Our observations indicate that mice that express a mutation in the Fas (CD95) gene had significantly worse HSK, and periocular disease, than did either wild type BALB/c or B6 mice. Gld mutants of these mouse strains were either no different than wild-type (BALB/c) or displayed an intermediated disease phenotype. Preliminary results also suggest that virus might persist in peripheral tissues slightly longer in BALB-lpr mice than in wild type controls, but similar persistence is also noted in BALB-gld mice. Suggesting that the disease phenotype in lpr mice might is not simply due to viral persistence, but that other mechanisms are involved. In order to better define the role that apoptotic molecules have during herpetic stromal keratitis we propose: To determine the specific contributions of Fas and FasL to ocular disease, protection from neuropathology, growth of virus, and maintenance of viral latency. Secondly, since we know that recurrent eye disease is not the same as primary HSK, we will perform similar studies in a recurrent model of HSK to evaluate the role of Fas and FasL in this form of the disease. We will also explore the efficacy of treating mice with a soluble form of Fas ligand as a means of more effectively controlling HSV-1 initiated inflammation. We believe these studies will enable us to better understand the role that the Fas-Fas ligand interaction plays during infectious disease of the cornea. PUBLIC HEALTH RELEVANCE The studies in this application are designed to better understand what mechanisms are involved in controlling the entry of immune cells (inflammation) into the cornea following infection with herpes simplex virus. This is important because the more inflammation that occurs the worse will be damage to the cornea. In addition, we will test a potential therapy that is designed to further control and possibly prevent inflammation.

描述（由申请人提供）：我们的实验室一直在研究Fas和Fas配体在角膜移植中的作用，并发表了几篇手稿，详细说明了这种相互作用对角膜同种异体移植成功和预防角膜新生血管形成的重要性。然而，这些凋亡分子在疱疹性眼病中发挥的作用仍有待充分阐明。关于该主题的唯一报告使用了不会产生重大疾病的病毒-小鼠品系组合。因此，凋亡分子在引起或预防 HSV-1 介导的眼部疾病中所起的确切作用尚不清楚。为了更清楚地了解这种情况，我们进行了初步研究，其中用 HSV-1 的 KOS 株感染 BALB/c、BALB-lpr（Fas 突变体）和 BALB-gld（Fas 配体突变体）小鼠，以及用 HSV-1 的 McKrae 株感染 C57BL/6 及其突变体，并监测角膜疾病和眼表病毒脱落。我们的观察表明，与野生型 BALB/c 或 B6 小鼠相比，表达 Fas (CD95) 基因突变的小鼠 HSK 和眼周疾病明显更严重。这些小鼠品系的 Gld 突变体要么与野生型 (BALB/c) 没有什么不同，要么表现出中间的疾病表型。初步结果还表明，BALB-lpr 小鼠中的病毒在外周组织中的持续时间可能比野生型对照小鼠稍长，但在 BALB-gld 小鼠中也发现了类似的持续时间。这表明 lpr 小鼠的疾病表型可能不仅仅是由于病毒持续存在，还涉及其他机制。为了更好地确定凋亡分子在疱疹性基质性角膜炎中的作用，我们建议：确定 Fas 和 FasL 对眼部疾病、神经病理学保护、病毒生长和病毒潜伏期维持的具体贡献。其次，由于我们知道复发性眼病与原发性 HSK 不同，因此我们将在复发性 HSK 模型中进行类似的研究，以评估 Fas 和 FasL 在这种疾病中的作用。我们还将探索用可溶形式的 Fas 配体治疗小鼠的功效，作为更有效控制 HSV-1 引发的炎症的一种手段。我们相信这些研究将使我们能够更好地了解 Fas-Fas 配体相互作用在角膜感染性疾病中所起的作用。公共卫生相关性 本申请中的研究旨在更好地了解在单纯疱疹病毒感染后控制免疫细胞（炎症）进入角膜的机制。这很重要，因为发生的炎症越多，对角膜的损害就越严重。此外，我们将测试一种旨在进一步控制并可能预防炎症的潜在疗法。

项目成果

Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice.

可溶性 Fas 配体的治疗用途可改善小鼠急性和复发性疱疹性基质角膜炎。

• DOI: 10.1167/iovs.15-16588
• 发表时间: 2015
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Rogge,Megan;Yin,Xiao-Tang;Godfrey,Lisa;Lakireddy,Priya;Potter,ChloeA;DelRosso,ChelseaR;Stuart,PatrickM
• 通讯作者: Stuart,PatrickM