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Heart development following genetic inactivation of Lmp4

Lmp4 基因失活后的心脏发育

基本信息

批准号：
7496622
负责人：
Jennifer K Krcmery
金额：
$ 2.78万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-10 至 2012-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496622
关键词：
Address Adult Affect Attention Behavior Binding Binding Proteins Biological Process Birth Boxing Cardiac Cell Nucleus Cell physiology Cells Chickens Coronary Coronary Vessels Cultured Cells Cytoplasm Defect Deformity Development Disease Embryo Embryonic Heart Enzymes Epicardium Family Galactosidase Genes Genetic Goals Heart Heart Atrium Hematoxylin and Eosin Staining Method Holt Oram syndrome Immunohistochemistry In Situ Hybridization In Vitro Knock-out Knockout Mice LIM Domain Protein Laboratories LacZ Genes Length Limb structure Lung Molecular Mus Mutant Strains Mice Mutation Myocardium Nuclear Organ Organogenesis Patients Pattern Phenotype Plasmids Pregnancy Range Reaction Reporter Genes Research Role Series Smooth Muscle Staging Staining method Stains Structure Syndrome Testing Tissues Transcriptional Regulation Transfection Upper Extremity Ventricular Septal Defects Viral Vector Week Wild Type Mouse Work Zebrafish cardiogenesis day dosage epithelial to mesenchymal transition in vivo insight loss of function member migration mouse model mutant novel protein expression protein function research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): The proposed studies determine the biological function of Lmp4 in heart development, alone and in association with Tbx5. This may provide new explanations for the wide range of phenotypes observed in Holt-Oram syndrome patients. To address the functional role of Lmp4 in heart development, we genetically inactivated the gene in the mouse. Utilizing the Lmp4 knockout mouse model, the proposed research will specifically test the hypothesis that Lmp4 functions as a regulator of Tbx5 subcellular localization in heart and coronary vasculature development. Lmp4 and Tbx5 expression will be analyzed in Lmp4 mutant mice, in comparison to wild type mice, providing insight into whether Lmp4 has a direct influence on Tbx5 subcellular distribution in an Lmp4 dosage dependent manner. The morphological phenotypes associated with genetic Lmp4 inactivation in the developing mouse heart will be analyzed in conjunction with Lmp4 and Tbx5 expression domains. This will determine whether the phenotypes are a direct result of compromised Lmp4 expression, or an indirect effect via altered Tbx5 subcellular localization. Primary epicardial cells cultured from homozygous Lmp4 mouse hearts will be used to determine the mechanistic function of Lmp4 alone and in association with Tbx5. The migratory behavior of the Lmp4 mutant cells will be assessed following rescue by transfection with full-length Lmp4 and rescue by transfection with Lmp4 constructs that lack the LIM3 domain Tbx5 binds. Lmp4 is a member of the PDZ-LIM family of proteins that function in critical biological processes such as organ development. Tbx5 is a member of the T-box family of transcription factors that has critical roles in many aspects of organogenesis. The overall goal of this proposed research is to elucidate the functional role of the interaction of Lmp4 and Tbx5 in heart development, which may provide new insights into heart/limb phenotypes observed in Holt-Oram syndrome.

描述（由申请方提供）：拟定的研究确定了Lmp 4单独和与Tbx 5联合在心脏发育中的生物学功能。这可能为Holt-Oram综合征患者中观察到的广泛表型提供新的解释。为了解决Lmp 4在心脏发育中的功能作用，我们在小鼠中遗传失活了该基因。利用Lmp 4基因敲除小鼠模型，拟议的研究将专门测试Lmp 4在心脏和冠状动脉血管发育中作为Tbx 5亚细胞定位的调节剂的假设。与野生型小鼠相比，将在Lmp 4突变小鼠中分析Lmp 4和Tbx 5表达，以提供对Lmp 4是否以Lmp 4剂量依赖性方式对Tbx 5亚细胞分布具有直接影响的了解。将结合Lmp 4和Tbx 5表达结构域分析发育中小鼠心脏中与遗传Lmp 4失活相关的形态学表型。这将确定表型是受损的Lmp 4表达的直接结果，还是通过改变Tbx 5亚细胞定位的间接影响。从纯合Lmp 4小鼠心脏培养的原代心外膜细胞将用于确定单独的Lmp 4和与Tbx 5联合的Lmp 4的机械功能。在通过用全长Lmp 4转染进行拯救和通过用缺乏Tbx 5结合的LIM 3结构域的Lmp 4构建体转染进行拯救之后，将评估Lmp 4突变细胞的迁移行为。Lmp 4是PDZ-LIM蛋白家族的成员，在器官发育等关键生物过程中发挥作用。Tbx 5是T-box转录因子家族的成员，在器官发生的许多方面具有关键作用。这项拟议研究的总体目标是阐明Lmp 4和Tbx 5在心脏发育中相互作用的功能作用，这可能为Holt-Oram综合征中观察到的心脏/肢体表型提供新的见解。