Characterization of alpha-actinin-4 deficient mice

α-肌动蛋白-4 缺陷小鼠的表征

基本信息

批准号：
7156209
负责人：
MARTIN R. POLLAK
金额：
$ 29.1万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7156209
关键词：
1-Phosphatidylinositol 3-Kinase Actinin Actins Adhesions Adult Alleles Behavior Biochemical Breeding Cell Adhesion Cells Clinical Markers Disease Embryo Family Fibroblasts Focal Adhesions Focal Segmental Glomerulosclerosis Functional disorder Gene Expression Genes Genetic Growth Histologic Homologous Gene Human Integrins Investigation Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Leukocyte Chemotaxis Leukocytes Mediating Modeling Morphology Movement Mus Mutant Strains Mice Mutate Mutation Natural History Onset of illness Pathway interactions Patients Perinatal mortality demographics Phenotype Play Property Proteins Proteinuria Research Personnel Role Signal Transduction Tissues Work alpha Actinin base cell motility cell type crosslink member mouse model mutant neonate podocyte programs protein expression research study

项目摘要

DESCRIPTION (provided by applicant): We have developed a mouse model deficient in Actn4, the murine homolog of the human focal segmental glomerulosclerosis gene ACTN4. These Actn4-/- mice develop proteinuria, abnormal glomerular podocyte morphology, and progressive kidney failure. Leukocyte chemotaxis, a sensitive indicator of cytoskeletal function, is altered in these mutant mice. We propose to use this model to better understand the role of Actn4-/-, with a particular focus on cell-matrix interactions and cell motility. We will: 1. Perform detailed characterization of the Actn4-/- and Actn4 mouse phenotypes. We will define the natural history of the phenotypic effect of this mutation. We will breed mice onto pure backgrounds to minimize Actn4-independent variability in the phenotype. We will characterize kidneys from these mice at histologic, biochemical, and protein expression levels. We will characterize mutant embryos and neonates in order to define the cause of increased perinatal mortality we observe in Actn4-/- mice. 2. Examine the effects of alpha-actinin-4 deficiency on cell adhesion and movement. We will assess the role of integrins in mediating altered leukocyte motility. We will examine the role of PI 3- kinase signaling in mediating this behavior. We will extend these experiments to other cell types, specifically, fibroblasts and podocytes. We will also examine the effect of alpha-actinin-4 deficiency cytoskeletal and growth properties of these cells. 3. Develop a "floxed" Actn4 allele in order to create a podocyte-specific Actn4 knockout mouse. This model will allow us to dissect the podocyte-specific contribution to the Actn4-/- phenotype and facilitate studies of the role of Actn4 in other cell types.

描述（由申请人提供）：我们已经开发了一种缺乏ACTN4的小鼠模型，ACTN4是人类局灶性节段性肾小球硬化基因ACTN4的鼠同源物。这些ACTN4 - / - 小鼠会形成蛋白尿，异常的肾小球足细胞形态和进行性肾衰竭。这些突变小鼠的白细胞趋化性是细胞骨架功能的敏感指标。我们建议使用此模型更好地了解ACTN4 - / - 的作用，并特别关注细胞 - 基质相互作用和细胞运动。我们将： 1。执行ACTN4 - / - 和ACTN4小鼠表型的详细表征。我们将定义该突变表型效应的自然史。我们将在纯背景上繁殖小鼠，以最大程度地减少表型中的ACTN4非依赖性变异性。我们将在组织学，生化和蛋白质表达水平上表征这些小鼠的肾脏。我们将表征突变的胚胎和新生儿，以定义我们在ACTN4 - / - 小鼠中观察到的围产期死亡率增加的原因。 2。检查α-肌动蛋白4缺乏对细胞粘附和运动的影响。我们将评估整联蛋白在介导改变的白细胞运动中的作用。我们将研究Pi 3-激酶信号传导在介导这种行为中的作用。我们将将这些实验扩展到其他细胞类型，特别是成纤维细胞和足细胞。我们还将检查这些细胞的α-肌动蛋白4缺乏细胞骨架和生长特性的作用。 3。开发一个“ Floxed” Actn4等位基因，以创建Podocyte特异性ACTN4敲除鼠标。该模型将使我们能够对ACTN4 - / - 表型的足细胞特异性贡献进行剖析，并促进对ACTN4在其他细胞类型中的作用的研究。