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: 7734588
• 负责人: Chi-Chao Chan
• 金额: $ 131.78万
• 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/7734588
• 关键词: Acute; Adverse effects; Age related macular degeneration; Animal Model; Animals; Annual Reports; Area; Autoantibodies; B-Cell Lymphomas; B-Lymphocytes; Biological Markers; Biological Models; Blindness; Bruch' s basal membrane structure; Cells; Cellular Membrane; Central Nervous System Lymphoma; Chemotherapy-Oncologic Procedure; Chlamydia; Chronic; Clinical; Collaborations; Complement Activation; Condition; Deposition; Development; Diagnosis; Disease; Dose; Drusen; Elevation; Endoplasmic Reticulum; Environmental Risk Factor; Etiology; Experimental Models; Eye; Eye Neoplasms; Eye diseases; Functional disorder; Gene Rearrangement; Goals; HIV; Helicobacter pylori; Hepatitis C virus; Human; Immunity; Immunohistochemistry; Immunologics; Immunophenotyping; Immunotherapy; Infectious Agent; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-10; Intraocular Lymphoma; Invaded; Learning; Lesion; Liquid substance; Literature; Location; Lymphoma; Malignant Neoplasms; Methotrexate; Microdissection; Modeling; Molecular; Molecular Analysis; Mus; Neoplasm Metastasis; Neoplasms; Ocular Toxoplasmosis; Oncogenes; Organism; Other Genetics; Papillomavirus; Pathogenesis; Pathology; Patients; Penetrance; Play; Polymerase Chain Reaction; Prevention therapy; Process; Proteins; Publishing; Reporting; Research; Resistance; Restriction fragment length polymorphism; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinal Neovascularization; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Serum; Simplexvirus; Specimen; Structure of retinal pigment epithelium; Syndrome; T-Cell Lymphoma; Techniques; Technology; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Suppression; Uvea; Uveitis; VHL protein; Vascular Endothelial Growth Factors; Von Hippel-Lindau Syndrome; Work; chemotherapy; cofactor; early onset; extracellular; fludarabine; hemangioblastoma; immunopathology; improved; macrophage; melanoma; microorganism; molecular pathology; neoplastic cell; novel; novel therapeutics; purine analog; sulfated glycoprotein 2; tumor; tumorigenesis

The identity and topographic location of ocular inflammatory, degenerated, and tumor cells and their products in patient specimens and animal samples are analyzed by routine pathology, pathophysiology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology such as microdissection combined with molecular techniques such as PCR, RT-PCR, and RFLP, allows us to provide more accurate pathological diagnosis (assessment) of the disease, and guide us in selecting an appropriate therapy for the patient. We generate and/or apply what we learn from various animal models with ocular disorders, so we can know the mechanisms of different ocular diseases. Using these animal models we can also access the efficacies of different therapeutic agents for various ocular diseases. This helps us to better understand disease pathogenesis and to better select therapies targeting specific diseases. In FY2008, we continued and accomplished the following in our research: 1. Ocular Lymphoma and Adnexal Tumors: We continue to confirm elevation of interleukin-10 in ocular fluids in patients with primary intraocular B-cell lymphoma and IgH gene rearrangements of ocular B-cell lymphoma cells. Chemotherapy regimens with high dose methotrexate are recommended for primary CNS lymphoma. Intraocular chemotherapy has the advantage of limited side effects and has been shown to be useful in primary intraocular lymphoma patients. We found that alterations in the transport of methotrexate across the cellular membrane might contribute to resistance following repeated intravitreal injection. The vast majority of primary intraocular lymphomas are malignant B-cells, while intraocular T-cell lymphomas are rare. We reported a case of metastatic T-cell lymphoma to the eye and demonstrated the utility of immunophenotyping and molecular analysis using microdissection and PCR, as critical adjunctive studies in patients presenting with masquerade syndrome. Vitreoretinal involvement, with no uveal involvement, was seen in this case, similar to many ocular metastatic T-cell lymphomas in the literature. This is intriguing since the uvea, rather than the retina, is the typical ocular tissue invaded in the majority of metastatic tumors, including systemic B-cell lymphoma. We also explore the role of infectious microorganisms (human papilloma virus, HIV, human herpes simplex virus-8, Helicobacter pylori, Chlamydia and hepatitis C virus) in ocular adnexal neoplasms. Multiple organisms may play a role in the etiology of certain ocular adnexal neoplasms by acting through similar mechanisms of oncogenesis, including chronic antigenic stimulation and the action of infectious oncogenes. However, similar to other human malignancies, the ultimate role of infectious agents in ocular adnexal neoplasms is most likely as a cofactor to the other genetic and environmental risk factors. 2. Molecular Pathology of Age-Related Macular Degeneration (AMD): While the clinical and histopathological features of AMD are well characterized, its etiology and pathogenesis remain unclear. Recent discoveries suggest a role for immunologic processes in AMD pathogenesis, including extracellular deposits (drusen) inside the Bruch membrane and beneath the retinal pigment epithelium (RPE), recruitment of macrophages (M2) for clearance of these deposits, complement activation, recruitment of tissue-destructive macrophages (M1), microglial activation and accumulation, and proinflammatory effects of chronic inflammation by microorganisms such as Chlamydia. Further studies are necessary to clarify the precise mechanisms and time course underlying AMD development and, in turn, develop novel therapies for the prevention and treatment of AMD. 3. New Pathology and Pathogenesis of Ocular Diseases: We reported a sizeable decrease of cluster expression in ocular hemangioblastomas associated with von Hippel-Lindau disease (VHL). Clusterin has potential important functions in tumor suppression by VHL protein, and thus may become a novel biomarker in ocular VHL tumors. We also found high vascular endothelial growth factor levels in retinal neovascularization as a manifestation of ocular VHL lesion. We detected serum anti-retinal autoantibodies in acute annular outer retinopathy. We provided the histopathologic evidence, for the first time, that fludarabine (a purine analog) directly induce toxicity to retinal ganglion and bipolar cells causing a rapidly progressive blindness. 4. Experimental Models for Various Ocular Diseases: We proved that Ccl2-/-/Cx3cr1-/- (DKO) mice showed a broad spectrum of AMD pathologies with early onset and high penetrance and possibly imply a role for certain inflammatory molecules, A2E, and endoplasmic reticulum proteins in AMD pathogenesis. The DKO mice present similar immunopathological profiles. Both innate and adaptive immunities play an important role in DKO retinal degeneration. In collaboration with Drs. Caspi, Gery, Hooks, and Nussenblatt of the NEI, and Dr. Restifo of the NCI, several new modes and mechanisms of ocular inflammation and immunotherapy in melanoma have been discovered and published. These are further described in their annual reports.

通过常规病理学，病理生理学，免疫组织化学和分子病理，分析了眼部炎症，退化和肿瘤细胞及其产物的身份和地形位置。 尖端技术（例如显微解剖）与PCR，RT-PCR和RFLP等分子技术相结合的应用，使我们能够对疾病提供更准确的病理诊断（评估），并指导我们为患者选择适当的治疗。 我们生成和/或应用我们从各种具有眼部疾病的动物模型中学到的知识，因此我们可以知道不同眼疾病的机制。 使用这些动物模型，我们还可以访问各种眼部疾病的不同治疗剂的功效。 这有助于我们更好地理解疾病发病机理，并更好地选择针对特定疾病的疗法。 在2008财年，我们在研究中继续并完成了以下内容： 1。眼淋巴瘤和附加肿瘤： 我们继续确认眼部B细胞淋巴瘤原发性B细胞淋巴瘤和眼部B细胞淋巴瘤细胞的IGH基因重排患者的Ocular-By液中白细胞介素-10的升高。 建议对原发性中枢神经系统淋巴瘤进行高剂量甲氨蝶呤的化学疗法方案。 眼内化疗具有有限的副作用，并且已被证明可用于原发性淋巴瘤患者。 我们发现，甲氨蝶呤在整个细胞膜上的转运改变可能会导致玻璃体内注射后的耐药性。 绝大多数原发性眼内淋巴瘤是恶性B细胞，而眼内T细胞淋巴瘤很少见。 我们报道了一种转移性T细胞淋巴瘤的病例，并证明了使用显微解剖和PCR进行免疫表型和分子分析的实用性，作为对伪装综合征的患者的重要辅助研究。 在这种情况下，玻璃体视网膜的参与没有卵巢的参与，类似于文献中许多眼部转移性T细胞淋巴瘤。这很吸引人，因为紫水紫色而不是视网膜是入侵大多数转移性肿瘤（包括全身性B细胞淋巴瘤）的典型眼组织。 我们还探讨了感染性微生物（人乳头瘤病毒，HIV，人类疱疹病毒8，幽门螺杆菌，衣原体和丙型肝炎病毒）在眼部辅助肿瘤中的作用。 多种生物可以通过通过相似的肿瘤发生机制作用，包括慢性抗原刺激和感染性癌基因的作用，在某些眼部附件肿瘤的病因中起作用。 但是，与其他人类恶性肿瘤类似，传染剂在眼部附件肿瘤中的最终作用很可能是其他遗传和环境风险因素的辅助因子。 2。年龄相关的黄斑变性（AMD）的分子病理： 尽管AMD的临床病理学特征和组织病理学特征是很好的特征，但其病因和发病机理尚不清楚。 Recent discoveries suggest a role for immunologic processes in AMD pathogenesis, including extracellular deposits (drusen) inside the Bruch membrane and beneath the retinal pigment epithelium (RPE), recruitment of macrophages (M2) for clearance of these deposits, complement activation, recruitment of tissue-destructive macrophages (M1), microglial activation and accumulation, and proinflammatory effects微生物（如衣原体）的慢性炎症。 需要进一步的研究来阐明AMD发展的确切机制和时间过程，进而开发用于预防和治疗AMD的新型疗法。 3。眼疾病的新病理和发病机理： 我们报道了与von Hippel-Lindau疾病（VHL）相关的眼血管细胞群中簇表达的大量降低。 簇蛋白在VHL蛋白抑制肿瘤中具有潜在的重要功能，因此可能成为眼部VHL肿瘤中的新型生物标志物。 我们还发现视网膜新血管化中高血管内皮生长因子水平是眼病变的表现。 我们在急性环形视网膜病变中检测到血清抗视网膜自身抗体。 我们首次提供了组织病理学的证据，即氟达拉滨（嘌呤类似物）直接引起对视网膜神经节的毒性，并引起双极细胞，从而引起快速渐进的失明。 4。各种眼部疾病的实验模型： 我们证明了CCL2 - / - /CX3CR1 - / - （DKO）小鼠显示出广泛的AMD病理，具有早期发作和高渗透率，可能暗示着某些炎症分子A2E，A2E和内质性网状蛋白在AMD病原体中的作用。 DKO小鼠具有类似的免疫病理学特征。 先天和适应性免疫在DKO视网膜变性中都起着重要作用。 与Drs合作。 NEI的Caspi，Gery，Hooks和Nussenblatt以及NCI的Restifo博士，黑色素瘤中眼部炎症和免疫疗法的几种新模式和机制。这些在年度报告中得到了进一步描述。

项目成果

Conjunctival involvement with T-cell prolymphocytic leukemia: report of a case and review of the literature.

T 细胞幼淋巴细胞白血病结膜受累：病例报告并文献复习。

• DOI: 10.1016/j.survophthal.2004.06.005
• 发表时间: 2004
• 期刊: Survey of ophthalmology
• 影响因子: 5.1
• 作者: Lee,SusanS;Robinson,MichaelR;Morris,JohnC;Mirtsching,BarryC;Shen,DeFen;Chan,Chi-Chao
• 通讯作者: Chan,Chi-Chao

Microdissection and gene rearrangement analysis of paraffin-embedded specimens of orbital malignant lymphoma.

眼眶恶性淋巴瘤石蜡包埋标本的显微切割和基因重排分析。

• DOI: 10.1007/s10384-003-0038-7
• 发表时间: 2004
• 期刊: Japanese journal of ophthalmology
• 影响因子: 2.4
• 作者: Miyanaga,Masaru;Kiyosawa,Motohiro;Takase,Hiroshi;Eishi,Yoshinobu;Shen,DeFen;Chan,Chi-Chao;Mochizuki,Manabu
• 通讯作者: Mochizuki,Manabu

Massive vascular endothelium growth factor (VEGF) expression in Eales' disease.

• DOI: 10.1055/s-2002-30662
• 发表时间: 2002-04
• 期刊: Klinische Monatsblatter fur Augenheilkunde
• 影响因子: 0.8
• 作者: Y. Perentes;C. Chan;E. Bovey;S. Uffer;C. Herbort

Mycobacterium-related ocular inflammatory disease: diagnosis and management.

分枝杆菌相关眼部炎症性疾病：诊断和治疗。

• 发表时间: 2006
• 期刊: Annals of the Academy of Medicine, Singapore
• 作者: Kurup,ShreeK;Chan,Chi-Chao
• 通讯作者: Chan,Chi-Chao

Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma.

• DOI: 10.1001/archopht.119.10.1518
• 发表时间: 2001-10
• 期刊: Archives of ophthalmology
• 作者: G. Velez;P. Yuan;C. Sung;G. Tansey;G. Reed;C. Chan;R. Nussenblatt;M. Robinson