Molecular Mechanisms of Peripheral Prion Pathogenesis

描述(申请人提供)：Prion疾病影响包括人类在内的许多物种，但目前还缺乏治疗这些总是致命的神经退行性疾病的方法。这项拟议中的研究的思想包括了解普恩在到达大脑之前是如何传播和繁殖的，在大脑中它们会造成神经退化和随后的死亡。尽管免疫系统通常帮助清除体内的感染，但Pron会反直觉地利用免疫系统中称为补体的特定部分来传播到复制部位。具体地说，如果你通过基因操作让小鼠缺乏某些补体蛋白，这些动物要么完全抵抗疾病，要么表现出延迟的疾病发病。免疫系统由两个主要分支组成：第一道防线称为先天免疫，另一条较慢但更具体的分支称为获得性免疫。补体主要通过识别宿主细胞上没有的病原体的共同模式，在人体抵御感染性病原体的第一道防线中发挥作用。考虑到Prion使用补体来传播疾病，其内部目标之一涉及通过表面等离子共振来表征自然来源的Prion和补体蛋白之间的相互作用，这是一种广泛用于研究分子相互作用的技术。找出与蛋白质结合强度最大的补体蛋白，可以为预防疾病进展提供治疗靶点。因子H抑制宿主组织的补体识别，从而在预防自身免疫中发挥作用。其他研究表明，因子H既能结合正常折叠的蛋白，也能结合错误折叠的蛋白。这些发现提出了一个问题，即H因子是否通过阻止补体识别而在限制Pron的传播方面发挥作用。文中描述的第二个目标将测试H因子通过结合Prion和抑制补体识别来预防Prion疾病的假设。如果H因子确实在普恩病毒病中起到这一作用，那么H因子缺乏的小鼠将比H因子充足的小鼠更快地死于普恩病毒疾病。如果是这样，那么过度表达或使用H因子治疗可能有助于限制疾病的进展。最终，拟议的项目与NINDS任务并行，通过了解神经疾病的原因和进展的共同目标，最终目标是为治愈提供潜在的治疗目标。

DESCRIPTION (provided by applicant): Prion diseases affect numerous species including humans, but a cure for these invariably fatal, neurodegenerative diseases is currently lacking. The ideology of the proposed research involves understanding how prions spread and propagate before they reach the brain where they inflict neurodegeneration and subsequent death. Although the immune system normally aids in clearing the body of infections, prions counter-intuitively utilize a specific part of the immune system termed Complement to spread to sites of replication. Specifically, if you genetically manipulate mice to lack certain Complement proteins, the animals either resist disease entirely or exhibit a delayed disease onset. The immune system consists of two main branches: the first line of defense, termed innate immunity, and a slower yet more specific branch termed adaptive immunity. Complement plays a role in the body's first line of defense against an infectious agent mainly through recognizing patterns common to pathogens yet absent on host cells. Considering prions use Complement to spread disease, one of the aims within involves characterizing the interaction between naturally derived prions and Complement proteins through surface plasmon resonance, a broadly used technology used for studying molecular interactions. Identifying the Complement proteins which directly bind proteins with the greatest strength could provide therapeutic targets for preventing disease progression. Factor H inhibits Complement recognition of host tissues and thus plays a role in preventing autoimmunity. Others have shown Factor H binds both normally folded as well as misfolded prion protein. These findings raise the question of whether Factor H plays a role in limiting the spread of prions through preventing Complement recognition. The second aim described within will test the hypothesis that Factor H prevents prion disease by binding prions and inhibiting Complement recognition. If Factor H indeed plays this role in prion disease, then mice deficient in Factor H will succumb to prion disease at a faster rate than Factor H sufficient mice. If so, then perhaps overexpression or treatment with Factor H could serve to limit disease progression. Ultimately, the proposed projects parallel the NINDS mission through the shared goal of understanding causes and progression of neurological diseases with the ultimate goal to provide potential therapeutic targets for a cure.