Structure determination by vibrational spectroscopy

 描述（由申请人提供）：“晚发性”阿尔茨海默病（LOAD）的“原因”尽管经过了数十年日益密集的研究，但在很大程度上仍然未知。目前有超过500万人患有这种疾病，它是美国第六大死亡原因，并且没有可用的治疗方法可以改变其无情的过程。该疾病的特征在于 在脑中聚集的腺苷酸肽作为原纤维，以及原纤维聚集在一起， 组织学上可观察到的由死亡神经元发出的斑块。我们假设，Aesthetic肽假设至少有几个不同的构象在形态上难以区分的原纤维，这些构象在其热力学稳定性不同。随着纤维的成熟，它们可能会接近越来越稳定的结构，因此在成熟过程中演变的光谱信号应该揭示决定稳定性的相互作用的性质。因此，我们的具体目标是将原纤维形成的条件与形成的原纤维的稳定性联系起来，并确定导致原纤维在脑组织中足够稳定的因素。这是美国国家卫生研究院赞助的研究资源宾夕法尼亚大学超快光学过程实验室的一个“驱动生物医学项目”。相关性：我们的方法有可能揭示控制阿尔茨海默病中淀粉样蛋白形成的特定化学机制，这将代表我们对其发病机制的理解向前迈出了一大步。

 DESCRIPTION (provided by applicant): The "cause" of "late-onset" Alzheimer's disease (LOAD) remains largely unknown despite decades of increasingly intense study. More than 5 million people currently have this disease, it is the 6th leading cause of death in the US, and there are no treatments available that alter its relentless course. The disease is characterized by the accumulation of Aß peptides in the brain as fibrils, and the collection of fibrils together as histologically observable plaques sounded by dead neurons. We hypothesize that Aß peptides assume at least several distinct conformations in morphologically indistinguishable fibrils, and that these conformations vary in their thermodynamic stability. It is likely that fibrils approach increasingly stable structures as they mature, so the spectroscopic signals that evolve in the course of maturation should reveal the nature of the interactions that determine stability. Accordingly, our specific aims are to link the conditions of fibril formation to the stability of te fibrils that form and determine the factors that lead to fibrils that are sufficiently stable to pesist in brain tissue. This is a "driving biomedical project" in the Ultrafast Optical Processes Laboratory at the University of Pennsylvania, an NIH-sponsored Research Resource. Relevance: Our approach has the potential to uncover specific chemical mechanisms that govern amyloid formation in Alzheimer's disease, which would represent a giant step forward in our understanding of its pathogenesis.