DEGENERATIVE AND DEMENTING DISEASES OF AGING

痴呆症是最可怕的疾病之一， 老年人经常受苦。 老年痴呆症（AD）是最常见的 常见的痴呆症 AD是一种神经退行性疾病， 这是未知的，除了一些家族病例。 对两个问题的研究 家族性和散发性AD的进展缓慢，部分原因是我们的 缺乏合适的动物模型。 相反，动物的可用性 朊病毒引起的神经退行性疾病的模型， 相对快速的进步。 事实上，朊病毒疾病已经成为 将理解迟发性CNS退行性疾病， 这一提案的重点。 在人类中，朊病毒疾病通常发生在 在老年人中，但其发病时间的机制尚不清楚。 最近的研究认为朊病毒病可能是蛋白质紊乱， 构象 旨在阐明机制的研究 细胞朊病毒蛋白（PrPc）转化为羊瘙痒病的过程 同种型（PrPsc）。 的实验与理论研究 PrPc和PrPsc的二级、三级和四级结构为 以及合成PrP肽。 为了促进这些 研究，将生产PrPc和PrPsc的重组抗体 可以区分PrP的不同构象。 PrP无细胞合成研究旨在开发系统 用于体外生成PRPSc，并结合 PrPsc的复性。 除了使用构象依赖性PrP 抗体研究PrPsc复性和无细胞合成，他们将 可用于研究PrPSc在散发和 家族性Creutzfeldt-Jakob病（CJD）。 每一个独立的或 羊瘙痒症朊病毒的“菌株”具有独特的PrPSc积累模式 这表明朊病毒多样性的分子基础存在于 细胞特异性合成的PrPSc积累表明， 朊病毒多样性的分子基础在于细胞特异性合成 的PrPSc。 家族性CJD最大病灶由PrP密码子200引起 在以色列的利比亚犹太人中发现了突变。 患者以及 利比亚犹太人的家庭成员的风险和未受影响的将进行研究。 这里提出的调查地址的分子机制 负责传染性，遗传性和散发性的发病机制 朊病毒疾病的形式。 不同的技能，人才和背景， 这项计划的研究人员提供了一个不寻常的机会， 以确定负责神经变性的分子机制， 朊病毒疾病 阐明脑细胞停止生长的机制 在朊病毒疾病中长时间延迟后功能和死亡可能提供新的 阐明更普遍的病因的方法 神经退行性疾病折磨老年人，包括AD。

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.