IDENTIFICATION AND CHARACTERIZATION OF FIRST MESSENGERS THAT REGULATE APP

监管应用程序的第一批信使的识别和特征

• 批准号: 6932685
• 负责人: Joseph D. Buxbaum
• 金额: $ 12.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932685
• 关键词: Alzheimer' s disease; aging; amyloid proteins; artificial chromosomes; biological signal transduction; electron microscopy; enzyme linked immunosorbent assay; genetically modified animals; growth factor receptors; human tissue; immunocytochemistry; ligands; neuropathology; posttranslational modifications; protein localization; protein protein interaction; protein structure function; pyramidal cells; tissue /cell culture

The deposition of beta-amyloid (Abeta) in the Alzheimer's brain has long been regarded as a potential causative agent in the progression of Alzheimer's disease (AD) pathology. Over the past 10 years, characterization of the proteolytic events leading to Abeta generation has been the object of rigorous and exhaustive investigation. It is now understood that processing of the amyloid precursor protein (APR) by a group of enzymes known as the secretases ultimately underlies the liberation of AS. As more is known about these enzymes, it becomes increasingly clear that they likely have many substrates and inhibiting them may have multiple biological effects. The central question of this proposal is which intercellular signals regulate regulate the cleavage of APP. The processing of APP resembles that of other transmembrane proteins. The most notable among these is that which exists between APP and Notch. Binding of Notch to any of its cognate ligands (ie delta, jagged, serrate) results incleavage of the Notch receptor and shedding of the extracellular domain. This regulated step is followed by cleavage by through regulated intramembranous processing (RIP), leading to the liberation of the Notch Intracellular Domain (NICD). NICD is then translocated to the nucleus where it acts as regulator of transcription. With Notch, it is binding of ligand that activates the processing secretases. It appears likely that specific activation of APP cleavage may be induced by the binding of ligand to APP (and, perhaps ligand binding to heterologous receptors). The Specific Aims are as follows: 1) Determine the identity of ligands that bind APP and regulate cleavage in a manner consistent with Notch processing; 2) Determine the potential for growth-factor receptors to regulate cleavage of APP; 3) Elucidate the potential molecular pathways through which APP ligands or growth-factor receptors regulate APP cleavage; and, 4) Determine the levels and distribution of first messenger pathways (including APP ligands and heterologous receptors and their ligands) that regulate APP processing in control and Alzheimer tissue.

β-淀粉样蛋白（Abeta）在阿尔茨海默病（AD）脑内的沉积长期以来被认为是阿尔茨海默病（AD）病理进展的潜在致病因子。在过去的10年中，导致Abeta生成的蛋白水解事件的表征一直是严格和详尽的研究对象。现在已经知道，淀粉样前体蛋白（APR）被一组称为分泌酶的酶加工，最终导致AS的释放。随着对这些酶的了解越来越多，越来越清楚的是，它们可能有许多底物，抑制它们可能会产生多种生物学效应。这一建议的核心问题是细胞间的信号调节 APP的加工类似于其他跨膜蛋白的加工。其中最值得注意的是存在于APP和Notch之间的。Notch与其任何同源配体（即δ、锯齿状、锯齿状）的结合导致Notch受体的裂解和胞外结构域的脱落。该调节步骤之后是通过调节的膜内加工（RIP）切割，导致Notch胞内结构域（NICD）的释放。然后，NICD被转移到细胞核，在那里它充当转录调节因子。对于Notch，是配体的结合激活了加工分泌酶。 APP裂解的特异性激活似乎可能是通过配体与APP的结合（以及可能是配体与异源受体的结合）诱导的。具体目的如下：1）确定与APP结合并以与Notch加工一致的方式调节切割的配体的身份; 2）确定生长因子受体与APP结合的潜力。 调节APP的裂解; 3）阐明APP配体或生长因子受体通过其调节APP切割的潜在分子途径;和4）确定在对照和阿尔茨海默病组织中调节APP加工的第一信使途径（包括APP配体和异源受体及其配体）的水平和分布。