AGING DISEASE--TRANSGENIC/VIROLOGIC/IMMUNOLOGIC STUDIES

传染性海绵状脑病(TSE)(Pron病、瘙痒病) 是一种致命的神经退行性疾病，发生在人类和动物身上。 这项资助的重点是阐明致病机制(S) 神经细胞损伤的致病因素及其分子利用 治疗和/或关于疾病的方法。我们假设 以海绵体增多症、星形细胞增多症、神经性疾病为特征的中枢神经系统疾病 死亡、神经缺失和异常异构体积聚(PrP/Sc) 从宿主编码的细胞PrP(PrP/c)由两个不同的 小路。第一种是通过PrP/sc在神经元中的直接积累。 然而，外源PrP/c的存在延迟/中止了 疾病。这项建议的一个主要目的是继续研究和 扩大外源性PrP/c在流产/治疗TSE中的评价 疾病。这项提案的第二个主要目的是评估 神经元损伤也是由旁观者(间接)效应造成的。肿瘤坏死因子- 阿尔法，一种与细胞凋亡有关的细胞因子，在 在瘙痒病期间的中枢神经系统。肿瘤坏死因子-α的表达与急性髓细胞白血病的发病平行 设计了临床症状和使用肿瘤坏死因子-αKo小鼠的实验 以确定其在疾病中的作用。此外，在Prion+(MPRP+)中 未接种PrP/Null(Ko)(PrP/Null)小鼠的小鼠瘙痒病 导致T淋巴细胞渗透到大脑中，这与 临床病程。初步实验表明，这需要一种 MHC I类Ko小鼠感染鼠瘙痒病的时间显著延长 与MHC相比，用于发展临床和组织学瘙痒病的试剂 I类充足的小鼠，强烈提示CD8+T细胞可能 与MHC I类相比，在瘙痒病的发病机制中起着重要作用 足够的小鼠，强烈表明CD8+T细胞可能有助于 瘙痒病的发病机制。PrP免疫耐受的谜团是 被重新评估。MHC分子和T细胞亚群在人类免疫缺陷中的作用 将研究TSE病的发病机制，以及PrP上的区域 经T细胞识别后确定。

Transmissible spongiform encephalopathies (TSE) (prion disease, scrapie) are fatal neurodegenerative diseases that occur in humans and animals. This grant's focus is on elucidating the pathogenic mechanism(s) contributing to the neuronal injury and on utilizing molecular approaches to treat and/or about disease. We hypothesize that the disease of the CNS characterize by spongiosis, astrocytosis, neural death, neural dropout and accumulation of an abnormal isoform (PrP/sc) from the host-encoded cellular PrP (PrP/c) occurs by two distinct pathways. The first is by direct accumulation of PrP/sc in neurons. However, the presence of exogenous PrP/c delays/aborts the onset of disease. A major aim of this proposal is to continue studies and to expand the evaluation of exogenous PrP/c in aborting/treating TSE disease. The second major aim of this proposal evaluates the possibility that neuronal injury also occurs from bystander (indirect) effects. TNF- alpha, a cytokine-implicated in apoptosis, is markedly increased in the CNS during scrapie disease. TNF-alpha expression parallels the onset of clinical symptoms and experiments using TNF-alpha ko mice are designed to determine its role in disease. In addition, in prion + (mPrP+) but not in prion/null (ko) (mPrP/null) mice, inoculation of murine scrapie leads to infiltration of T lymphocytes into the brain that parallels the clinical course of disease. Initial experiments show it takes a significantly longer time for MHC class I ko mice given murine scrapie agent to develop clinical and histological scrapie when compared to MHC class I sufficient mice, strongly suggesting that CD8+ T cells may contribute to the pathogenesis of scrapie when compared to MHC class I sufficient mice, strongly suggesting that CD8+ T cells may contribute to the pathogenesis of scrapie. The enigma of immune tolerance to PrP is to be re-evaluated. The role played by MHC molecules and T cell subsets in the pathogenesis of TSE disease will be investigated, and regions on PrP recognized by T cell determined.