Core--Pathology/Immunology

佛罗里达大学的分子病理学和免疫学中心协助研究人员参与旨在逆转和/或预防肝脏疾病、代谢紊乱、囊性纤维化、α-1-抗胰蛋白酶（AAT）缺乏症和糖尿病的基因治疗项目。具体而言，核心通过进行病理学和免疫学分析来支持这些研究，这些分析表征了宿主的免疫系统和细胞/组织对实验和临床前研究中提出或目前使用的载体和转基因的反应。这一目标将通过执行三个具体目标来实现：1）确定病毒载体和成体干细胞植入的部位以及宿主组织中关于给药部位、载体剂量和治疗持续时间的毒性。2)确定潜在受益 转基因表达在1-抗胰蛋白酶（AAT）缺乏、糖原累积病和其它遗传和代谢紊乱的啮齿动物模型中的作用。3)在研究长期治疗性基因转移和表达的研究中，确定给予动物的rAAV转基因产物和衣壳分子的免疫原性。这样的研究是至关重要的，以评估rAAV治疗是否成功地改善了给药部位内的促炎环境，并确定rAAV治疗诱导急性炎症或细胞毒性或在给药部位外血原性扩散的程度。形态学研究的集中化和组织病理学研究的标准化 和毒理学决定因素，使得能够严格评估宿主毒性作为这些治疗算法的结果。程序包括小鼠、大鼠、兔、灵长类动物和猫模型中的标准免疫测定、组织病理学、组织化学、免疫组织化学和FISH。除了提供保证治疗安全性的关键要素外，核心还应提供增强肝细胞基因递送试验可行性和有效性的信息。

The Molecular Pathology and Immunology Core of the University of Florida assists investigators participating in gene therapy projects aimed at reversing and/or preventing liver diseases, metabolic disorders, cystic fibrosis, alpha-1-antitrypsin (AAT) deficiency, and diabetes. Specifically, the Core supports these investigations by performing pathological and immunological analyses that characterize the host's immune system and cell/tissue responses to vectors and transgenes proposed for or currently used in experimental and preclinical studies. This goal will be accomplished by performance of three specific aims: 1) Determine the site(s) of viral vector and adult stem cell engraftment and toxicity in host tissues with respect to administration site, vector dose, and treatment duration. 2) Determine the potential beneficial effects of transgene expression in rodent models of 1-antitrypsin (AAT) deficiency, glycogen storage diseases, and other genetic and metabolic disorders. 3) Determine the immunogenicity of rAAV transgene products and capsid molecules administered to animals in studies investigating long-term therapeutic gene transfer and expression. Such studies are vital in order to evaluate whether rAAV therapy successfully ameliorates the pro-inflammatory environment within the site of administration and to determine the extent to which rAAV therapy induces acute inflammation or cytotoxicity or spreads hematogenously outside the site of administration. Centralization of the morphological studies, and standardization of the histopathological and toxicological determinants, enables rigorous assessment of host toxicity as a result of these treatment algorithms. Procedures include standard immunoassays, histopathology, histochemistry, immunohistochemistry, and FISH in mouse, rat, rabbit, primate, and cat models. In addition to providing a critical element for assurance of therapeutic safety, the Core should provide information that will enhance the feasibility and efficacy of gene delivery trials to the hepatocyte.