DEGENERATIVE AND DEMENTING DISEASES OF AGING

痴呆症是最令人恐惧的疾病之一， 老年人经常遭受痛苦。阿尔茨海默病(AD)是最常见的 常见的痴呆症。AD是一种神经退行性疾病，其病因为 除了一些家族性病例外，这一点是未知的。关于这两个问题的研究 家族性和零星形式的AD进展缓慢，部分原因是我们的 缺乏合适的动物模型。相比之下，动物的可获得性 由普恩引起的神经退行性疾病的模型导致了 相对较快的进步。事实上，Prion病已经成为最 Will了解迟发性中枢神经系统退行性疾病 这项提案的重点。在人类中，普恩病毒病通常发生。 但支配其发病时间的机制尚不清楚。 最近的研究认为，Pron疾病可能是蛋白质的紊乱。 构象。旨在阐明其机制的研究 细胞内的蛋白(PrPc)转化为瘙痒病 提出了异构体(PrPsc)。实验与理论研究相结合 PrPc和PrPsc As的二级、三级和四级结构 以及合成PrP多肽的计划。为了促进这些 研究，将产生PrPc和PrPsc的重组抗体 它可以区分PrP的不同构象。 PrP的无细胞合成研究旨在开发系统 用于体外生成PRPSc，并结合对 PrPsc的复性。除了使用构象依赖的PrP 研究PrPsc复性和无细胞合成的抗体，他们将 被用来研究PrPSc在散发性和 家族性克雅病(CJD)每个不同的分离物或 PrPSc的“品系”具有独特的PrPSc积累模式 这表明，Pron多样性的分子基础存在于 PrPSc积聚的细胞特异性合成表明 Pron多样性的分子基础存在于细胞特异性合成 PrPSc.PrP密码子200引起的家族性CJD最大病灶 在居住在以色列的利比亚犹太人中发现了突变。患者以及 将对处于危险中的利比亚犹太人和未受影响的家庭成员进行研究。 这里提出的研究涉及分子机制。 负责感染性、遗传性和散发性的发病机制 普恩病毒病的各种形式。不同的技能、才华和背景 拟议项目中的调查人员提供了一个不同寻常的机会 为了明确神经退行性变的分子机制 普恩病毒病。脑细胞停滞机制的阐明 在长时间的延迟后在普恩病毒病中发挥作用并死亡可能提供新的 阐明更为普遍的肺炎的病因的方法 困扰老年人的神经退行性疾病，包括阿尔茨海默病。

Dementing diseases are among the most dreaded afflictions from which older people frequently suffer. Alzheimer's disease (AD) is the most common dementia. AD is a neurodegenerative disorder, the etiology of which is unknown expect for some familial cases. Studies on both the familial and sporadic forms of AD have been slow, in part, due to our lack of suitable animal models. In contrast, the availability of animal models for neurodegenerative diseases caused by prions has led to relatively rapid advances. Indeed, prion diseases have become the most will understood CNS degenerative disorders of delayed onset and they are the focus of this proposal. In humans, prion diseases generally occur in older adults but the mechanisms governing their time onset is unknown. Recent studies argue that prion diseases may be disorders of protein conformation. Investigations directed toward elucidating the mechanism of conversion of the cellular prion protein (PrPc) into the scrapie isoform (PrPsc) are proposed. Experimental and theoretical studies on the secondary, tertiary and quartenary structures of PrPc and PrPsc as well as synthetic PrP peptides are planned. To facilitate these investigations, recombinant antibodies to PrPc and PrPsc will be produced which can discriminate between the different conformations of PrP. Studies on the cell-free synthesis of PrP are designed to develop systems for the in vitro generation of PRPSc in conjunction with studies on the renaturation of PrPsc. Besides using conformational dependent PrP antibodies to study PrPsc renaturation and cell-free synthesis, they will be used to investigate the patterns of PrPSc accumulation in sporadic and familial Creutzfeldt-Jakob disease (CJD). Each distinct isolate or "strain" of scrapie prions has unique pattern of PrPSc accumulation suggesting that the molecular basis of prion diversity resides in the cell-specific synthesis of PrPSc accumulation suggesting that the molecular basis of prion diversity resides in the cell-specific synthesis of PrPSc. The largest focus of familial CJD cause by a PrP codon 200 mutation is found in Libyan Jews living in Israel. Patients as well as at risk and unaffected family members of Libyan Jews will be studied. The investigations proposed here address the molecular mechanism responsible for the pathogenesis of the infectious, genetic and sporadic forms of prion diseases. The diverse skills, talents and background of the investigators in the proposed program offer an unusual opportunity to define the molecular mechanisms responsible for neurodegeneration in prion diseases. Elucidation of the mechanisms by which brain cells cease to function and die in prion diseases after a long delay may offer new approaches to elucidating the etiologies of more prevalent neurodegenerative disorders afflicting older people, including AD.