Primary Intraocular Lymphoma and Animal Models

原发性眼内淋巴瘤和动物模型

• 批准号: 7594071
• 负责人: ROBERT B. NUSSENBLATT
• 金额: $ 2.6万
• 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/7594071
• 关键词: Animal Model; Animals; Award; Base Pairing; Cancer Etiology; Cerebrospinal Fluid; Code; Collaborations; DNA Sequence; Decision Making; Development; Disease; Disease model; Early Diagnosis; Educational workshop; Frequencies; Genes; Genetic; Genome; Histopathology; Human; Human Characteristics; Human Genome; Immune system; Immunotoxins; Individual; Inheritance Patterns; Interleukin-10; Interleukins; Intraocular Lymphoma; Malignant Neoplasms; Methods; Modeling; Molecular; Mus; Mutation; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Patients; Population; Predisposing Factor; Prevalence; Pseudomonas; Publishing; Research; Sampling; Single Nucleotide Polymorphism; Source; Staging; Therapeutic Agents; Tissues; Toxic effect; United States National Institutes of Health; Variant; Vitreous humor; base; bench to bedside; genetic linkage analysis; human tissue; interest; killings; mouse model; novel; novel therapeutics; positional cloning; prognostic; tumor

There is no known underlying genetic defect predisposing patients to develop primary intraocular lymphoma (PIOL). Discovery of genetic factors predisposing to the development of PIOL would be of benefit for early diagnosis, prognostic staging, and development of novel treatments for PIOL. Until recently, genetic approaches to investigate the etiology of cancer have relied upon methods utilizing linkage based on traditional Mendelian inheritance patterns. It is probable that many diseases are a consequence of multiple genetic factors, and are therefore less amenable to study using traditional methods of linkage analysis and positional cloning to isolate single genes. Single nucleotide polymorphisms (SNPs) are the most common sources of variation in the human genome. SNPs are single-base differences in the DNA sequence that can be observed among individuals in a population. A SNP is defined on the basis of a frequency of at least 1% prevalence in one or more populations. SNPs are present throughout the genome at an average frequency of 1/1000 base pairs. We propose to analyze the frequency of SNPs specifically within the coding frames of biologically plausible genes responsible for function of the innate immune system. The interleukins are a specific pathway of interest because previous research has demonstrated derangements in the ratios of interleukins 10 and 6 in the vitreous humor and spinal fluid of patients with PIOL, leading to the hypothesis that altered function or expression of these or other interleukins could permit the development of this rare malignancy. Samples continue to be collected, but as no results have yet been obtained. We hosted a workshop on this subject at the NIH this past fiscal year with the results recently published. Since recruitment for this study was very slow we have made the decision to suspend this study. However, we received a Bench to Bedside award to begin to investigate the use of a CD-22/pseudomonas construct in order to kill intraocular tumor. Initial studies have been promising with our plan to carry these further in animal studies and ultimately to the treatment of patients. From 2005 to 2007, we have made substantial progress in establishing a murine model to mimic human PIOL as well as searching for novel and effective therapy for this disease. We have established a mouse model that resembles human PIOL at the level of histopathology and molecular pathogenesis. We demonstrated that the model shares several hall mark characteristics of human PIOL and is ideal for further studying the molecular mechanisms of human PIOL. Furthermore, in collaboration with NCI, we found that a recently developed immunotoxin (HA22) can eradicate the tumor with minimal toxicity and is potentially a novel therapeutic agent for treating human PIOL. Currently, we are investigating the toxicity of HA22 to ocular tissues using a rabbit model.

没有已知的潜在遗传缺陷易感患者 发展原发性淋巴瘤（PIOL）。遗传的发现 偏爱PIOL的因素对 早期诊断，预后分期和新疗法的发展 用于偶然。直到最近，遗传方法研究病因 癌症的依赖于基于传统的联系的方法 孟德尔的继承模式。许多疾病很可能是 多种遗传因素的结果，因此不太适合 使用传统的链接分析和位置方法研究 克隆到分离单个基因。单核苷酸多态性（SNP） 是人类基因组中最常见的变异来源。 SNP是 DNA序列的单基差差异可以观察到 人口中的个人。根据频率定义SNP 在一个或多个人群中至少有1％的患病率。 SNP存在 在整个基因组中，平均频率为1/1000个碱基对。我们 建议在编码中专门分析SNP的频率 负责功能的生物学上合理基因的框架 先天免疫系统。白细胞表是一种特定的感兴趣途径 因为以前的研究表明了比率的危险 患者的玻璃体幽默和脊髓液中的白细胞介素10和6 使用PIOL，导致了改变功能或表达的假设 这些或其他白纹可以允许这种罕见的发展 恶性。样本继续被收集，但由于尚无结果 已获得。我们过去在NIH举办了有关此主题的研讨会 财政年度，结果最近发布了。自招募以来 这项研究非常慢，我们决定暂停这项研究。 但是，我们获得了床头的长凳奖，以开始调查使用 CD-22/假单胞菌构建是为了杀死眼内肿瘤。最初的 我们的计划有望在动物中进一步携带这些研究 研究并最终治疗患者。 从2005年到2007年，我们在建立一个 鼠模型以模仿人类的偶氮以及寻找新颖和 该疾病的有效疗法。我们已经建立了一个鼠标模型 在组织病理学水平和分子水平上类似于人类PIOL 发病。我们证明该模型有几个大厅标记 人类PIOL的特征，非常适合进一步研究 人类偶氮的分子机制。此外，与 NCI，我们发现最近开发的免疫毒素（HA22）可以消除 毒性最小的肿瘤可能是一种新型治疗 治疗人类偶氮的代理。目前，我们正在研究HA22的毒性 使用兔模型到眼组织。