Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

 描述（由申请人提供）：仅蛋白质或朊病毒假说假定细胞生理学的变化是由宿主编码的蛋白质（朊病毒）重折叠成改变其正常功能的替代构象引起的。这一过程的核心事件是 这些替代构象体组装成有序的淀粉样蛋白聚集体，其与相同蛋白质的其他构象体缔合、结合并由此模板化重折叠。然而，淀粉样蛋白的积累是细胞表型变化的一个很差的预测因子，我们最近的研究表明，朊病毒，更普遍的淀粉样蛋白，生物学可能来自于独特的稳态小生境，这些小生境是由多个以前未预料到的，目前对系统的限制了解甚少的交叉所产生的。目前的知识差距是该领域进展的关键障碍，因为我们无法解释，预测并因此利用朊病毒错误折叠及其体内表型效应之间的联系。我们的长期目标是通过开发一个基于系统的理解朊病毒生物学，整合蛋白质质量控制途径，朊病毒蛋白质序列和构象，细胞生物学，以弥合这一差距。为此，我们正在利用朊病毒生物学的神秘方面，包括序列变异，显性负抑制，细胞骨架相互作用，菌株优势和朊病毒相互作用，以揭示贡献者和机制，定义系统中的平衡，创建不同的稳态壁龛兼容每个构象状态，并诱导沿沿着这些连续的过渡。

 DESCRIPTION (provided by applicant): The protein-only or prion hypothesis posits that changes in cellular physiology arise from the refolding of host- encoded proteins (prions) to alternative conformations that alter their normal functions. A central event in this process is the assembly of these alternative conformers into ordered amyloid aggregates, which associate with, incorporate, and thereby template the refolding other conformers of the same protein. However, the accumulation of amyloid is a poor predictor of changes in cellular phenotype, and our recent studies reveal that prion, and more generally amyloid, biology likely arises from unique homeostatic niches created by an intersection of multiple, previously unanticipated, and currently poorly understood constraints of the system. This current gap in knowledge is a critical barrier to progress in the field because we are unable to explain, predict and therefore exploit the link between prion misfolding and its phenotypic effects in vivo. Our long-term goal is to bridge this gap by developing a system-based understanding of prion biology that integrates protein quality control pathways, prion protein sequence and conformation, and cell biology. Toward this end, we are exploiting enigmatic aspects of prion biology including sequence variants, dominant negative inhibition, cytoskeletal interactions, strain dominance and prion interactions to reveal the contributors and mechanisms that define balance in the system, create distinct homeostatic niches compatible with each conformational state, and induce transitions along these continuums.