Molecular Mechanisms of Peripheral Prion Pathogenesis

描述（由申请人提供）：朊病毒疾病影响包括人类在内的许多物种，但目前缺乏治疗这些致命的神经退行性疾病的方法。这项拟议研究的思想包括了解朊病毒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变性和随后的死亡。虽然免疫系统通常有助于清除体内的感染，但朊病毒利用免疫系统中称为补体的特定部分扩散到复制部位，这与直觉相反。具体来说，如果你对老鼠进行基因操作，使其缺乏某些补体蛋白，这些动物要么完全抵抗疾病，要么表现出疾病发作的延迟。免疫系统由两个主要分支组成：第一道防线，称为先天免疫，以及一个较慢但更具体的分支，称为适应性免疫。补体在人体抵御感染因子的第一道防线中发挥作用，主要是通过识别病原体共有的模式，但在宿主细胞中却没有。考虑到朊病毒利用补体传播疾病，本研究的目的之一是通过表面等离子体共振（一种广泛用于研究分子相互作用的技术）来表征天然衍生的朊病毒与补体蛋白之间的相互作用。鉴定出直接结合蛋白强度最大的补体蛋白，可为预防疾病进展提供治疗靶点。H因子抑制宿主组织的补体识别，从而在预防自身免疫中起作用。其他研究表明因子H可以结合正常折叠和错误折叠的朊病毒蛋白。这些发现提出了一个问题，即因子H是否通过阻止补体识别来限制朊病毒的传播。本文描述的第二个目标将检验因子H通过结合朊病毒和抑制补体识别来预防朊病毒疾病的假设。如果因子H确实在朊病毒疾病中起着这种作用，那么缺乏因子H的小鼠将比因子H充足的小鼠更快地死于朊病毒疾病。如果是这样，那么也许过度表达或用因子H治疗可以限制疾病的进展。最终，拟议的项目通过了解神经系统疾病的病因和进展这一共同目标与NINDS的使命并行，最终目标是提供潜在的治疗靶点。

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.