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）：该项目的目的是检验最近发现的假定多胞膜内蛋白酶 (IMPAS1/IMP1) 是大脑发育的关键调节因子的假设。我们假设 IMPAS1 通过控制脂质依赖性进化保守信号系统发挥作用。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。 PS 在早期发育过程中是 Notch1 受体介导的信号传导所必需的。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），其结构与早老素相关。 IMP 蛋白在体内的功能尚不清楚。我们发现 Ce-imp-2 与人类 hIMP1 同源，是秀丽隐杆线虫特定发育途径的关键调节因子。我们最近获得了mIMP1敲除小鼠产生的初步数据，并初步观察到mIMP1敲除动物的主要表型是严重的大脑发育缺陷：无脑畸形（大脑过度生长）和无脑畸形（大脑耗竭）。在这个项目中，我们建议测试以下假设。 1）IMP1的功能是控制神经形成。 2) hIMP1失活将导致大脑异常，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部病变的常见原因。 3) IMPAS蛋白是控制发育的特定脂质依赖性信号通路的新的重要成分。我们预计该通路与 Wnt 下游信号传导有关，IMP1 的缺陷会损害该信号传导，导致神经管发育关键阶段程序性细胞死亡过程的时空变化。这些假设将通过追求以下具体目标进行检验： 目标 1. 确定 IMPAS1 在神经形成和发育中的作用。我们将完成敲除 mIMP1-/- 小鼠品系的产生，并将阐明小鼠中因 IMP1 功能丧失而引起的表型。将对脑和非脑表型 IMP1 缺陷的动物和野生型动物进行详细比较，以预测由 IMP1 控制的假定途径。我们还将确定外脑畸形和无脑畸形是否是相关的表型；以及哪些遗传环境因素可能改变 IMP1 敲除动物的异常神经系统，导致无脑畸形，这是人类常见的先天性脑缺陷。目的2.阐明体内IMP1基因调控的分子通路。通过使用分子信号分析、检查特定标记和转录效应子的时空表达，我们将确定 IMP1 缺陷动物中的分子改变是否与正常神经系统必需的信号传导受损的动物中发现的分子改变相似，以及 IMP1 是否与 Wnt 信号传导相互作用。目标 3. 确定 IMP1 缺陷动物中程序性细胞死亡的调节是否受损。我们将确定 IMP1 缺乏是否与大脑发育过程中程序性细胞死亡、分化和增殖过程的缺陷有关。我们将确定 IMP1 是否通过 Wnt 依赖性或独立途径对细胞凋亡的调节很重要。 公共健康相关性：对最近发现的多次跨膜蛋白 (IMPAS1/IMP1) 的研究将深入了解正常和异常大脑发育以及程序性细胞死亡调节所涉及的机制。 IMP1 蛋白的基因在结构上与阿尔茨海默病早老素相关。我们在初步数据中发现，这种蛋白质可能是胚胎发生的神经管基本事件形成的重要调节因子。我们计划提供证据，证明这种蛋白质在中枢神经系统发育和神经系统信号传导中的重要作用，如果神经系统被破坏，就会导致无脑畸形，这是人类最常见的先天性大脑缺陷。