Function of intramembrane aspartic protease

膜内天冬氨酸蛋白酶的功能

• 批准号: 7666816
• 负责人: EVGENY I ROGAEV
• 金额: $ 33.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666816
• 关键词: Aging-Related Process; Alzheimer' s Disease; Anencephaly; Animal Model; Animals; Apoptosis; Apoptotic; Aspartic Endopeptidases; Biological Assay; Brain; Brain Pathology; Caenorhabditis elegans; Cell Death; Cell physiology; Cells; Data; Defect; Development; Embryo; Embryonic Development; Environmental Risk Factor; Event; Exencephalies; Family; Generations; Genes; Genetic; Growth; Human; Indium; Integral Membrane Protein; Invertebrates; Knock-out; Knockout Mice; Lead; Lipids; Mammals; Mitochondria; Modeling; Molecular; Molting; Mouse Strains; Mus; Mutation; Names; Neural Tube Defects; Neural Tube Development; Neural tube; Orthologous Gene; Pathway interactions; Peptide Hydrolases; Perinatal; Phenotype; Population; Process; Property; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Spinal Cord; Staging; System; Testing; Vertebrates; Wild Animals; brain tissue; familial Alzheimer disease; in utero; in vivo; insight; knockout animal; loss of function; member; mouse model; notch protein; novel; positional cloning; presenilin; presenilin-1; presenilin-2; public health relevance; receptor; receptor-mediated signaling

DESCRIPTION (provided by applicant): The objective of this project is to test the hypothesis that a recently identified putative polytopic intramembrane protease (IMPAS1/IMP1) is a critical regulator of brain development. We postulate that IMPAS1 acts via control of a lipid-dependent evolutionary-conserved signaling system. Mutations in two homologous presenilin genes, PS1 and PS2, are the cause of familial Alzheimer's disease (AD). PSs are required for Notch1 receptor-mediated signaling in early development. We and others have recently identified a novel family of diverged proteins (IMPAS (IMP) or SPP/SPPL) structurally related to presenilins. The function of IMP proteins in vivo is unknown. We have found that Ce-imp-2, homologous to human hIMP1, is a critical regulator of a specific development pathway in C. elegans. We recently obtained preliminary data for the generation of knockout mice for mIMP1 and made primary observations that the major phenotypes of the mIMP1 knockout animals are severe brain development defects: exencephaly (brain overgrowth) and anencephaly (brain depletion). In this project we propose to test the following hypotheses. 1) The function of IMP1 is to control neurulation. 2) Inactivation of hIMP1 will lead to brain abnormalities, including neural tube defects and anencephaly, a common cause of perinatal lethality or severe brain pathology in humans. 3) IMPAS proteins are novel essential components of the specific lipid-dependent signaling pathways controlling development. We anticipate that this pathway is connected to Wnt- downstream signaling, and deficiency in IMP1 impairs this signaling leading to spatio-temporal alterations in processes of programmed cell death during a critical stage of neural tube development. The hypotheses will be tested by pursuing the following specific aims: Aim 1. To determine the role of IMPAS1 in neurulation and development. We will complete the generation of knockout mIMP1-/- mouse strains and will elucidate phenotypes induced by a loss of function of IMP1 in mice. Detailed comparisons of both brain and non-brain phenotype IMP1-deficient animals and wild type animals will be made to predict the putative pathway controlled by IMP1. We will also determine whether exencephaly and anencephaly are related phenotypes; and what genetic-environmental factors may modify the abnormal neurulation in IMP1 knockout animals leading to anencephaly, a common congenital brain defect in humans. Aim 2. To elucidate molecular pathways regulated by IMP1 gene in vivo. Using molecular signaling assays, examination of spatial-temporal expression of specific markers and transcriptional effectors we will identify whether molecular alterations in IMP1-deficiency animals are similar to those found in animals with impaired signaling essential for normal neurulation and whether IMP1 interact with Wnt- signaling. Aim 3. To determine whether regulation of programmed cell death is impaired in IMP1-deficient animals. We will determine whether IMP1- deficiency is associated with defects in the processes of programmed cell death, differentiation and proliferation during brain development. We will determine whether IMP1 is important for regulation of apoptosis via Wnt-dependent or independent pathway. PUBLIC HEALTH RELEVANCE: The study of recently identified multipass transmembrane protein (IMPAS1/IMP1) will provide insight into the mechanisms involved in normal and abnormal brain development and regulation of programmed cell death. The gene for the IMP1 protein is structurally related to Alzheimer's disease presenilins. We found in our preliminary data that this protein may be an essential regulator in the formation of the neural tube fundamental event of embryogenesis. We plan to provide evidence for the essential role of this protein in CNS development and signaling in neurulation, which if disrupted, underlies anencephaly, a most common congenital brain defect in humans.

描述(由申请人提供)：本项目的目标是验证最近发现的一种假定的多表位膜内蛋白酶(IMPAS1/IMP1)是大脑发育的关键调节因子的假设。我们推测，IMPAS1通过控制脂质依赖的进化保守的信号系统发挥作用。两个同源早老素基因PS1和PS2的突变是家族性阿尔茨海默病(AD)的原因。在发育早期，PSS是Notch1受体介导的信号转导所必需的。我们和其他人最近发现了一个新的分化蛋白家族(IMPAS(IMP)或SPP/SPPL)，在结构上与早老素相关。IMP蛋白在体内的功能尚不清楚。我们已经发现，与人hIMP1同源的Ce-imp-2是线虫特定发育途径的关键调节因子。我们最近获得了mIMP1基因敲除小鼠产生的初步数据，并初步观察到mIMP1基因敲除动物的主要表型是严重的脑发育缺陷：脑外发育缺陷(脑过度生长)和无脑发育(脑耗竭)。在这个项目中，我们建议检验以下假设。1)IMP1的功能是控制神经发生。2)hIMP1失活会导致脑部异常，包括神经管缺陷和无脑畸形，这是人类围产期死亡或严重脑病理的常见原因。3)IMPAS蛋白是控制发育的特定脂质依赖信号通路的新的基本成分。我们推测这一途径与Wnt下游信号通路有关，IMP1的缺失会损害这一信号通路，导致神经管发育关键阶段细胞程序性死亡过程的时空变化。这些假说将通过追求以下特定目标来检验：目的1.确定IMPAS1在神经形成和发育中的作用。我们将完成mIMP1-/-基因敲除小鼠品系的产生，并将阐明IMP1功能丧失在小鼠中诱导的表型。将对脑和非脑表型IMP1缺陷动物和野生型动物进行详细比较，以预测IMP1控制的可能途径。我们还将确定外脑畸形和无脑畸形是否相关的表型；以及哪些遗传环境因素可能会改变IMP1基因敲除动物中导致无脑的异常神经形成，无脑是人类常见的先天性脑缺陷。目的2.阐明IMP1基因在体内调控的分子途径。通过分子信号分析、特异性标志物和转录效应物的时空表达检测，我们将确定IMP1缺陷动物的分子变化是否类似于正常神经形成所必需的信号受损动物的分子变化，以及IMP1是否与Wnt信号相互作用。目的3.确定IMP1基因缺陷动物对程序性细胞死亡的调节是否受损。我们将确定IMP1缺陷是否与脑发育过程中程序性细胞死亡、分化和增殖过程中的缺陷有关。我们将确定IMP1是否通过Wnt依赖或独立的途径对细胞凋亡起重要调节作用。公共卫生相关性：最近发现的多通路跨膜蛋白(IMPAS1/IMP1)的研究将有助于深入了解正常和异常脑发育以及调节程序性细胞死亡的机制。IMP1蛋白的基因在结构上与阿尔茨海默病早老素有关。我们在我们的初步数据中发现，该蛋白可能是胚胎发生的神经管基本事件形成中的一个必不可少的调节因子。我们计划为这种蛋白在中枢神经系统发育和神经形成信号中的重要作用提供证据，如果神经形成受到干扰，无脑是人类最常见的先天性脑缺陷。