AbetaPP Influences Cerebral Thrombosis

AbetaPP 影响脑血栓形成

• 批准号: 8641800
• 负责人: William E. Van Nostrand
• 金额: $ 39.35万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641800
• 关键词: Acute; Alzheimer' s Disease; Amyloid; Asses; Behavioral; Binding; Biological; Blood Vessels; Brain; Brain hemorrhage; Carotid Artery Thrombosis; Cause of Death; Cerebral Ischemia; Cerebral Thrombosis; Cerebral hemisphere hemorrhage; Cerebrum; Chronic; Chronic Disease; Country; Cytoprotection; Disease; Event; Exhibits; Experimental Models; Funding; Gene Mutation; Genes; Image; Injury; Investigation; Ischemic Stroke; Knock-in Mouse; Knockout Mice; Ligand Binding; N-terminal; Outcome; Peptide Hydrolases; Physiological; Property; Protease Inhibitor; Protein Isoforms; Protein Precursors; Proteins; Role; Severities; Staging; Stroke; Structure; Therapeutic Agents; Thrombosis; Time; Transgenic Mice; amyloid pathology; base; chronic stroke; disability; in vivo; in vivo Model; insight; novel; response

DESCRIPTION (provided by applicant): The amyloid ¿-protein precursor (A¿PP) is highly expressed in brain although its physiological functions remain poorly understood. Many functional domains have been identified on secreted forms of A¿PP proteins that could participate in variety of neuroprotective activities ranging from proteinase inhibition to ligand binding to cytoprotection. For example, it is known that shortly following stroke there is a marked increase in the expression of A¿PP suggesting that it may serve a protective function in response to this acute deleterious event. During the previous funding period we investigated the role of the Kunitz proteinase inhibitor (KPI) domain, contained in the 751/770 isoforms of secreted A¿PP (sA¿PP), in regulating thrombosis that occurs during the initial stages of cerebral vascular injury. Indeed, for the first time we unequivocally demonstrated that the KPI activity of sA¿PP-751/770 limits the extent of thrombosis associated with in vivo models of carotid artery thrombosis, cerebral hemorrhage, and focal cerebral ischemia. Despite these significant findings regarding in vivo functions of the KPI domain of sA¿PP other important activities are likely associated with other biologically active domains present on sA¿PP proteins in response to acute cerebral injuries including ischemic and hemorrhagic stroke and chronic disorders such as Alzheimer's disease (AD). Specifically, the N-terminal region of A¿PP (A¿PP18-119), upstream from the KPI domain, is a highly structured, naturally occurring fragment that possesses potential neuroprotective functions that could influence the consequences of different acute and chronic cerebral insults. Thus, the overall hypothesis that forms the basis of this competitive renewal is that the N-terminal region A¿P18-119 is neuroprotective in response to acute and chronic cerebral injuries. Whereas previously we focused on the cerebral function of the KPI domain of sA¿PP the broad objective of this competitive renewal is to investigate the functions of the upstream, N-terminal region of sA¿PP in vivo in the brain. We plan to implement a combination of in vivo studies to investigate if the N-terminus of A¿PP provides protection from the deleterious consequences of acute cerebral vascular injuries including ischemic and hemorrhagic stroke and more chronic cerebral insults associated with AD-like amyloid pathologies. Our studies will utilize novel gene mutation knock in and transgenic mouse lines related to A¿PP activities subjected to experimental models of acute and chronic cerebral insults and evaluated for short-term and long-term imaging, pathological, and behavioral outcomes. Completion of these studies will yield new insight into biological activities and potential neuroprotective functions of the N-terminus of A¿PP in these injury situations. Finally, A¿PP18-119, and fragments thereof, could provide the basis of therapeutic agents to ameliorate the deleterious consequences of acute ischemic and hemorrhagic stroke as well as more chronic amyloid pathologies associated with AD and related disorders.

描述（由申请人提供）：淀粉样蛋白前体（A <$PP）在脑中高度表达，但其生理功能仍知之甚少。许多功能域已被确定分泌形式的A？PP蛋白，可以参与各种神经保护活动，从蛋白酶抑制配体结合细胞保护。例如，已知在中风后不久， A？PP表达的增加表明它可能对这种急性有害事件起保护作用。在上一个资助期间，我们研究了Kunitz蛋白酶抑制剂（KPI）结构域（包含在分泌型A <$PP（sA <$PP）的751/770亚型中）在调节脑血管损伤初始阶段发生的血栓形成中的作用。事实上，我们第一次明确地证明了sA <$PP-751/770的KPI活性限制了与颈动脉血栓形成、脑出血和局灶性脑缺血的体内模型相关的血栓形成的程度。尽管这些关于sA <$PP的KPI结构域的体内功能的重要发现，其他重要活性可能与sA <$PP蛋白上存在的其他生物活性结构域相关，以响应急性脑损伤，包括缺血性和出血性中风以及慢性疾病，如阿尔茨海默病（AD）。 具体而言，A <$PP的N-末端区域（A <$PP 18 -119），KPI结构域上游，是一个高度结构化的，天然存在的片段，具有潜在的神经保护功能，可能会影响不同的急性和慢性脑损伤的后果。因此，形成这种竞争性更新的基础的总体假设是，N-末端区域A？P18-119对急性和慢性脑损伤具有神经保护作用。而以前我们专注于脑功能的KPI结构域的sA <$PP的竞争性更新的广泛目标是调查的上游，N-末端区域的sA <$PP在体内的大脑中的功能。我们计划实施一系列体内研究，以调查A？PP的N-末端是否能保护急性脑血管损伤（包括缺血性和出血性卒中）以及与AD样淀粉样病变相关的慢性脑损伤的有害后果。我们的研究将利用新的基因突变敲入和转基因小鼠品系相关的A <$PP活动受到急性和慢性脑损伤的实验模型，并评估短期和长期的成像，病理和行为的结果。这些研究的完成将产生新的见解生物活性和潜在的神经保护功能的N-末端的A？PP在这些损伤的情况下。最后，A PP 18 -119及其片段可以提供治疗剂的基础，以改善急性缺血性和出血性中风以及与AD和相关病症相关的更多慢性淀粉样蛋白病理学的有害后果。