ROLES OF VASCULAR AMYLOID BETA PROTEIN PRECURSOR

拟议研究的目标是双重的，并反映了研究 PN的生物化学、功能特性和细胞生物学领域- 2/AbetaPP目前由两项研究拨款资助。首先， PN-2/AbetaPP与凝血因子的生化相互作用 被调查。具体地说，本提案将侧重于研究 凝血因子X1a与PN-2/AbetaPP的相互作用 以及高分子量激肽原的作用和血管紧张素转换酶 这些相互作用上的生物表面。此外，还描述了 金黄色葡萄球菌的蛋白水解酶抑制和潜在抗凝血活性 AbetaPP相关基因的重组kunitz型蛋白酶抑制因子结构域 同源同源的计划是为了更好地理解 该蛋白与PN2/AbetaPP同源。第二，在某种程度上不同，但 相关和重要的一系列研究，PN-2/AbetaPP表达和 人死后脑组织在脑血管中的加工 并在培养的脑血管平滑肌细胞中进行研究。 这一系列的研究将开始阐明PN-2/AbetaPP是如何 在脑血管系统中通常可以作为抗凝剂，以及如何 可能与脑出血患者异常相关。 患有一种与阿尔茨海默氏症有关的罕见疾病，称为 遗传性脑出血伴淀粉样变性-荷兰型。更好 对PN-的生物化学和脑血管细胞生物学的认识 2/AbetaPP将提供对其正常功能的洞察以及 该蛋白在某些疾病中的病理生化和病理生理学研究 各州。

The objectives of the proposed studies are two-fold and reflect research areas in the biochemistry, functional properties, and cell biology of PN- 2/AbetaPP that are currently funded by two research grants. First, the biochemical interactions between PN-2/AbetaPP and coagulation factors will be investigated. Specifically, the present proposal will focus on studies concerning interactions between coagulation factor X1a and PN-2/AbetaPP and the effects of high molecular weight kininogen and the effects of biologic surfaces on these interactions. In addition, characterization of the protease inhibitory and potential anticoagulant properties of a recombinant Kunitz-type protease inhibitor domain of a related AbetaPP- homolog are planned to better understand the functional relatedness of this homolog protein to PN2/AbetaPP. Second, in a somewhat different, but related and important series of studies, PN-2/AbetaPP expression and processing in cerebral blood vessels from postmortem human brain tissue and in cultured cerebrovascular smooth muscle cells will be investigated. These series of investigations will begin to elucidate how PN-2/AbetaPP may normally serve as an anticoagulant in the cerebrovasculature and how it may abnormally be involved with intracerebral hemorrhaging in patients with a rare disorder that is related to Alzheimer's disease known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. Better understanding of the biochemistry and cerebrovascular cell biology of PN- 2/AbetaPP will provide insight into its normal function as well as the patho-biochemistry and pathophysiology of this protein in certain disease states.