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Regulation of APP Processing by Par-4

Par-4 对 APP 处理的规定

基本信息

批准号：
7152490
负责人：
QING GUO
金额：
$ 16.5万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7152490
关键词：
Abeta synthesis Address Adverse effects Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Apoptosis Apoptotic Binding Calcium Calpain Caspase Caspase-1 Cathepsins Cell Death Cell Line Cells Complex Condition Data Death Domain Disruption Dominant-Negative Mutation Endogenous Factors Endopeptidases Endoplasmic Reticulum Event Extracellular Space Homeostasis Human In Vitro Knock-in Mouse Lead Leucine Zippers Localized Maps Mediating Medicine Mus Mutation Nature Nervous system structure Neuroglia Neurons PAWR gene PAWR protein Pathogenesis Pathway interactions Peptide Hydrolases Play Process Production Prostate Protein Overexpression Proteins Reagent Regulation Research Personnel Role Series Solutions Testing Thapsigargin Therapeutic Transgenic Organisms alpha secretase amyloid peptide amyloid precursor protein processing extracellular in vivo mitochondrial dysfunction mouse model mutant neuron apoptosis neuronal survival neuroprotection neurotoxic novel novel therapeutics peptide A presenilin-1 programs promoter response secretase synaptic function tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): We recently identified the leucine zipper protein Par-4 (prostate apoptosis response-4) as a novel cell death promoting protein associated with pathogenesis of Alzheimer's disease (AD). Importantly, we have found that Par-4 may participate in regulation of Abeta production through a caspase-dependent pathway in transfected IMR-32 cells (Guo Q. et al., Nature Medicine 1998; 4(8): 957-962, Guo Q. et al., J. Biol. Chem., 2001; 276: 16040-4). Disruption of intracellular calcium homeostasis may lead to aberrant induction of Par-4 and abnormal processing of beta amyloid precursor protein (APP). These data suggest that Par-4 may be a novel regulator of APP processing. Most recently, we found that Par-4 interacts directly with APP, and alter Abeta secretion. These data strongly indicate that Par-4 regulates APP processing by at least two different mechanisms: (a) by caspase- and calcium-dependent pathways that is activated during apoptotic process, and (b) through direct physical interaction with APP. AATF is a novel leucine zipper protein that is expressed in neurons. We found AATF binds directly to Par-4 and confers neuroprotective actions, indicating that AATF might be an endogenous regulator of Par-4 activity. The proposed studies will employ a series of in vitro and in vivo approaches to test the following hypotheses: (1) Par-4 plays an essential role in aberrant APP processing of APP after initiation of apoptotic cascades; (2) Par-4 alters APP processing during apoptosis through a calcium-dependent pathway; (3) Par-4 directly interacts with APP and alters intracellular Abeta production and/or extracellular pool of secreted APPs and Abeta under apoptotic and/or nonapoptotic conditions; (4) AATF is a novel interaction partner of Par-4 and functions as an endogenous negative regulator of Par-4 activity in APP processing. The proposed studies may establish Par-4 as a novel regulator of APP processing. Inhibition of Par-4 activity by enhancing AATF expression and/or manipulating Par-4/APP interaction may provide novel therapeutic implications for Alzheimer's disease.

描述（由申请人提供）：我们最近鉴定了亮氨酸拉链蛋白Par-4（前列腺凋亡反应-4）作为与阿尔茨海默病（AD）发病机制相关的新的细胞死亡促进蛋白。重要的是，我们已经发现Par-4可以通过转染的IMR-32细胞中的半胱天冬酶依赖性途径参与调节Abeta产生（Guo Q.例如，Nature Medicine 1998; 4（8）：957-962，Guo Q.例如，J. Biol. Chem.，2001; 276：16040-4）。细胞内钙稳态的破坏可能导致Par-4的异常诱导和β淀粉样前体蛋白（APP）的异常加工。这些数据表明，Par-4可能是APP加工的一种新的调节剂。最近，我们发现Par-4直接与APP相互作用，并改变Abeta分泌。这些数据强烈地表明Par-4通过至少两种不同的机制调节APP加工：（a）通过在凋亡过程中被激活的半胱天冬酶和钙依赖性途径，以及（B）通过与APP的直接物理相互作用。AATF是在神经元中表达的新型亮氨酸拉链蛋白。我们发现AATF直接与Par-4结合并赋予神经保护作用，表明AATF可能是Par-4活性的内源性调节剂。本研究将采用一系列的体内外实验方法来验证以下假设：（1）Par-4在APP的异常加工过程中起重要作用：（2）Par-4通过钙依赖性途径改变APP在凋亡过程中的加工;（3）Par-4直接与APP相互作用，并在凋亡和/或非凋亡条件下改变细胞内A β的产生和/或分泌的APP和A β的细胞外库;（4）AATF是Par-4的一种新的相互作用伙伴，在APP加工过程中起着Par-4活性的内源性负调节剂的作用。拟议的研究可能建立Par-4作为APP加工的新调节剂。通过增强AATF表达和/或操纵Par-4/APP相互作用来抑制Par-4活性可能为阿尔茨海默病提供新的治疗意义。