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以下假设：最近确定的推定的多重膜内蛋白酶（IMPAS1/IMP1）是大脑发育的关键调节剂。我们假设IMPAS1通过控制脂质依赖性进化保守的信号传导系统起作用。两个同源蛋白基因PS1和PS2的突变是家族性阿尔茨海默氏病（AD）的原因。 Notch1受体介导的信号在早期发育中需要PSS。我们和其他人最近确定了一种与老年蛋白相关的新型分歧蛋白（IMPA（IMP）或SPP/SPPL）家族。 IMP蛋白在体内的功能尚不清楚。我们发现，与Human HISP1同源的CE-IMP-2是秀丽隐杆线虫特定发展途径的关键调节剂。最近，我们获得了用于MIMP1的基因敲除小鼠的初步数据，并主要观察到MIMP1敲除动物的主要表型是严重的脑发育缺陷：脑外伤（大脑过度生长）和厌氧（脑消耗）。在这个项目中，我们建议检验以下假设。 1）IMP1的功能是控制神经元。 2）HIMP1的失活将导致脑部异常，包括神经管缺陷和Ancephaly，这是人类围产期致死性或严重脑部病理的常见原因。 3）IMPAS蛋白是控制发育开发的特定脂质信号通路的新型基本组成部分。我们预计该途径与Wnt-下游信号连接在一起，而IMP1的缺陷会损害这种信号传导，从而导致神经管发育的关键阶段的程序性细胞死亡过程中的时空变化。假设将通过追求以下特定目的来检验：目的1。确定IMPAS1在神经和发育中的作用。我们将完成敲除MIMP1 - / - 小鼠菌株的产生，并阐明由小鼠中IMP1功能丧失引起的表型。将对大脑和非脑表型IMP1缺乏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excephaly和Ancephaly是否是相关的表型。哪些遗传环境因素可能会改变IMP1基因敲除动物的异常神经化，导致Ancephaly，这是人类常见的先天性大脑缺陷。目的2。阐明由Imp1基因在体内调节的分子途径。使用分子信号传导测定，检查特定标记和转录效应子的空间表达，我们将确定IMP1缺陷动物中的分子改变是否与正常神经信号障碍的动物中发现的动物相似，而IMP1是否与WNT信号相互作用。目的3。确定在缺陷的动物中是否会损害程序性细胞死亡的调节。我们将确定不足是否与编程细胞死亡，分化和大脑发育过程中的扩散过程中的缺陷有关。我们将确定IMP1对于通过WNT依赖性或独立途径调节凋亡是否重要。 公共卫生相关性：对最近确定的多通跨膜蛋白（IMPAS1/IMP1）的研究将洞悉涉及正常和异常脑发育和调节程序性细胞死亡的机制。 IMP1蛋白的基因与阿尔茨海默氏病的结构相关。我们在初步数据中发现，该蛋白可能是形成神经管的基本事件的必不可少的调节剂。我们计划提供证据证明该蛋白在CNS发育和信号传导中的基本作用，如果破坏了Ancephaly的基础，这是人类中最常见的先天性大脑缺陷。