Molecular And Immunopathology Of Experimental And Clinical Ocular Diseases

实验和临床眼部疾病的分子和免疫病理学

• 批准号: 8339745
• 负责人: Chi-Chao Chan
• 金额: $ 149.47万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8339745
• 关键词: Adult; Affect; Age; Age related macular degeneration; Animal Model; Annual Reports; Anti-Inflammatory Agents; Apoptosis; Area; B-Cell Lymphomas; Biological Models; Blindness; CX3CL1 gene; Candidate Disease Gene; Cells; Choroidal Neovascularization; Clinical; Collaborations; Copy Number Polymorphism; DNA Repair; Data; Development; Diagnosis; Diet; Disease; Drusen; Elderly; Elements; Endotoxins; Etiology; Experimental Models; Exudative age-related macular degeneration; Eye; Eye Neoplasms; Eye diseases; Genetic; Genotype; Goals; Granuloma; Hereditary Disease; Histopathology; Human; Human T-lymphotropic virus 1; Immunohistochemistry; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-17; Intraocular Lymphoma; Invaded; Investigation; Knowledge; Learning; Lesion; Link; Liquid substance; Lymphoma; Mediating; Microdissection; Microglia; Mitochondria; Modeling; Molecular; Molecular Analysis; Mus; Naloxone; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Allergy and Infectious Disease; Neoplasm Metastasis; Neoplasms; Nerve Degeneration; Nodule; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Publishing; Race; Reporting; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Lymphoma; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Safety; Series; Single Nucleotide Polymorphism; Smoking; Specimen; Sympathetic Ophthalmia; T-Cell Leukemia; T-Cell Lymphoma; Techniques; Technology; Therapeutic Agents; Thromboplastin; Tissues; United States; Uveitis; Vascular Endothelial Growth Factors; Von Hippel-Lindau Syndrome; Work; angiogenesis; animal tissue; autoimmune uveitis; cancer cell; chemokine; cholesterol trafficking; conventional therapy; cytokine; effective therapy; gene therapy; geographic atrophy; immunopathology; improved; leukemia/lymphoma; macrophage; molecular pathology; novel; novel therapeutics; photoreceptor degeneration; ultraviolet damage

We identify and topographically localize inflammatory, degenerative, and malignant cells, as well as their products in patient specimens and animal tissues. We analyze the cells and their products mainly by routine pathology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology, such as microdissection combined with molecular techniques including PCR, RT-PCR, RQ-PCR and genotyping, allows us to provide more accurate pathological diagnosis (assessment) and pathogenesis of the disease. It also guides us in selecting the most appropriate treatment for patients. We learn a great deal about the mechanisms of different ocular diseases from various animal models. Using animal models, we can also assess the efficacy of different therapeutic agents for various ocular diseases. This helps us better understand disease mechanisms and select specific therapies targeting particular diseases for our patients. In FY2011, we accomplished the following in our research: 1. Molecular Pathology of Age-Related Macular Degeneration (AMD): AMD is the leading cause of vision loss among the elderly in the United States, and the number of individuals affected is expected to increase 50% by the year 2020. The pathology of AMD is characterized with the accumulation of drusen, RPE and photoreceptor degeneration, geographic atrophy, and/or exudation with choroidal neovascularization. While several risk factors, including age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Treatment options for geographic atrophy AMD are extremely limited and for exudative/neovascular AMD include intravitreal injections of anti-vascular endothelial growth factor (VEGF). Current knowledge has revealed that AMD development is strongly influenced by genetic factors. We and other investigators have reported significant associations between AMD and single nucleotide polymorphisms in CFH, CX3CR1, and ARMS2/HtrA1 over the past few years. Growing evidence also suggests that inflammatory and immunological elements (e.g., macrophages and microglia), apoptosis, cholesterol trafficking, angiogenesis (e.g., VEGF expression), and oxidative stress (e.g., the role of mitochondria) play an important role in AMD development. In FY2011, using a duplex RT-PCR copy number genotyping approach, we evaluated copy number variations in 131 patients with exudative/neovascular AMD, but did not find definitive associations in 8 highly associated AMD candidate genes. We reported an increase of tissue factor expression in our murine model (Ccl2/Cx3cr1 double deficient mice) and human AMD lesions. We demonstrated that naloxone ameliorated retinal lesions of the Ccl2/Cx3cr1 double deficient mice via its inhibitory effect on microglia, and that AAV-5 mediated sFLT01 gene therapy arrested retinal lesions of these mice. In addition, we published a comprehensive review on the role of anti-inflammatory agents in AMD treatment. Conventional therapy that focuses solely on inhibiting angiogenesis may not be optimal because of the inflammatory involvement in AMD. Anti-inflammatory agents, which target specific inflammatory pathways and molecules, could be used as promising adjunct agents combined with anti-VEGF therapy for exudative neovascular AMD and potential therapies for geographic atrophy AMD. More studies are required to evaluate the efficacy and safety of the anti-inflammatory agents. 2. Ocular Lymphoma: We retrospectively reviewed a series of systemic metastatic retinal lymphoma cases at the NEI from 1991 to 2009. They had similar clinical presentations as primary vitreoretinal lymphoma. Systemic T-cell lymphomas that invade the retina and vitreous are more aggressive than systemic B-cell lymphoma. Molecular analysis is more useful than vitreous cytokine levels for the diagnosis of this metastasis. We reported ocular manifestations and pathology of adult T-cell leukemia/lymphoma associated with human T-cell lymphotropic virus type 1 (HTLV-1). 3. New Pathology and Pathogenesis of Ocular Diseases: We reported ophthalmic manifestations and histopathology including novel retinal degenerative findings of xeroderma pigmentosa. The new findings illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina. We conducted the first investigation of inflammatory cytokines and chemokines in 15 eyes with sympathetic ophthalmia (SO) and revealed predominant M1 macrophages in choroidal granulomas and Dalen-Fuchs nodules. High levels of Il-17 were expressed within granulomas and presence of Th1 in non-granulomatous inflammation. Targeting Th1, M1 and IL-17 may represent effective therapy for SO. 4. Experimental Models for Various Ocular Diseases: In collaboration with Drs. Caspi, Egwuagu, Hejtmancik, and Nussenblatt of the NEI, Drs. Robert Adelstein and Warren Leonard of NHLBI, Dr. Nicholas Restifo of NCI, Dr. Philip Murphy of NIAID, and Dr. Charles Venditti of NHGRI, different models and mechanisms of ocular inflammation and genetic diseases have been evaluated and published. The data is further described in the annual reports of these senior investigators.

我们在患者标本和动物组织中识别并在地形上定位炎症，退化性和恶性细胞及其产物。我们主要通过常规病理，免疫组织化学和分子病理分析细胞及其产物。 尖端技术的应用，例如显微解剖结合了包括PCR，RT-PCR，RQ-PCR和基因分型在内的分子技术，使我们能够提供更准确的病理诊断（评估）和疾病发病机理。 它还指导我们为患者选择最合适的治疗方法。 我们了解了来自各种动物模型的不同眼疾病的机制。 使用动物模型，我们还可以评估不同治疗剂对各种眼部疾病的疗效。 这有助于我们更好地理解疾病机制，并选择针对患者特定疾病的特定疗法。 在2011财年，我们在研究中完成了以下内容： 1。与年龄相关的黄斑变性（AMD）的分子病理： AMD是美国老年人视力丧失的主要原因，到2020年，受影响的个体的数量预计将增加50％。AMD的病理学的特征是Drusen，RPE和感光体退化，地理萎缩，以及/或因脉络膜新血管生长的渗出。 尽管包括年龄，种族，吸烟和饮食在内的几个危险因素与AMD有关，但该疾病的病因和发病机理仍然在很大程度上不清楚。 地理萎缩AMD的治疗选择极为有限，对于渗出/新生血管的AMD包括玻璃体内注射抗血管内皮生长因子（VEGF）。 当前的知识表明，AMD发展受遗传因素的强烈影响。 在过去的几年中，我们和其他研究人员报告了CFH，CX3CR1和ARMS2/HTRA1的AMD和单核苷酸多态性之间的显着关联。 越来越多的证据还表明，炎症和免疫学因素（例如巨噬细胞和小胶质细胞），凋亡，胆固醇贩运，血管生成（例如VEGF表达）以及氧化应激（例如，线粒体的作用）在AMD发育中起重要作用。 在2011财年，使用双链RT-PCR拷贝数基因分型方法，我们评估了131例渗出性/新生AMD患者的拷贝数变化，但在8个高度关联的AMD候选基因中没有发现明确的关联。 我们报道了我们的鼠模型（CCL2/CX3CR1双重缺陷小鼠）和人AMD病变中组织因子表达的增加。 我们证明了纳洛酮通过其对小胶质细胞的抑制作用改善了CCL2/CX3CR1双重缺陷小鼠的视网膜病变，并且AAV-5介导的SFLT01基因治疗阻止了这些小鼠的视网膜病变。 此外，我们对抗炎药在AMD治疗中的作用进行了全面综述。 由于AMD的炎症参与，仅关注仅抑制血管生成的常规疗法可能不是最佳的。 靶向特定炎症途径和分子的抗炎剂可用作有前途的辅助药物以及抗VEGF疗法的渗透性新生血管AMD和对地理萎缩AMD的潜在疗法。 需要更多的研究来评估抗炎药的功效和安全性。 2。眼淋巴瘤： 从1991年到2009年，我们回顾性地回顾了NEI的一系列全身转移性视网膜淋巴瘤病例。它们具有与原发性玻璃体视网膜淋巴瘤相似的临床表现。侵入视网膜和玻璃体的全身性T细胞淋巴瘤比全身性B细胞淋巴瘤更具侵略性。 分子分析比玻璃体细胞因子水平更有用，用于诊断该转移。 我们报道了与人类T细胞淋巴细胞型1型（HTLV-1）相关的成年T细胞白血病/淋巴瘤的眼部表现和病理。 3。眼疾病的新病理和发病机理： 我们报道了眼科表现和组织病理学，包括静脉皮肤病的新型视网膜退行性发现。 新发现说明了DNA修复在保护眼睛免受视网膜紫外线损伤和神经变性的作用。 我们在15眼中对炎症性细胞因子和趋化因子进行了首次研究，其中15眼（SO）（SO）（SO），并揭示了脉络膜肉芽肿和Dalen-Fuchs结节中的主要M1巨噬细胞。 高水平的IL-17在颗粒中表达，在非肉芽肿性炎症中TH1的存在。 靶向TH1，M1和IL-17可能代表SO的有效治疗。 4。各种眼部疾病的实验模型： 与Drs合作。 Caspi，Egwuagu，Hejtmancik和Nei的Nussenblatt博士。 NHLBI的Robert Adelstein和Warren Leonard，NCI的Nicholas Restifo博士，Niaid的Philip Murphy博士以及NHGRI的Charles Venditti博士，眼部炎症和遗传疾病的不同模型和机制已得到评估并发表。 这些高级研究人员的年度报告进一步描述了数据。