New mechanisms of heterotaxy and congenital heart disease: nucleoporins at cilia

异位性与先天性心脏病的新机制：纤毛的核孔蛋白

• 批准号: 8889146
• 负责人: MARTINA BRUECKNER
• 金额: $ 79.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889146
• 关键词: Affect; Candidate Disease Gene; Cardiac; Cardiac development; Cardiovascular Diseases; Categories; Cause of Death; Cell Culture Techniques; Cell Cycle Regulation; Cell Line; Cell Nucleus; Cells; Child; Cilia; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Copy Number Polymorphism; Custom; Cytoplasm; Data; Development; Diffusion; Disease; Embryo; Embryonic Development; Ensure; Epidermis; Eukaryota; Europe; Event; Gene Expression; Genes; Genetic; Genetic Counseling; Genomics; Goals; Heart; Heart failure; Human; Human Genetics; Image; Imagery; Incidence; Infant; Infant Mortality; Label; Lateral; Left; Light; Mammalian Cell; Mesoderm; Microscope; Modeling; Molecular; Morphogenesis; Nanostructures; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Operative Surgical Procedures; Organogenesis; Outcome; Parents; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Play; Proteins; Resolution; Role; Scientist; Signal Transduction; Situs Inversus; Structure; Technology; Testing; Xenopus; base; cardiogenesis; congenital heart disorder; improved; infant morbidity/mortality; interest; knock-down; light microscopy; model development; nanoscale; nanostructured; novel; outcome forecast; public health relevance; research study; scaffold; stoichiometry; success

 DESCRIPTION (provided by applicant): Congenital heart disease is one of the major causes of infant mortality and morbidity in the US. However, we know little about the genetic causes of this disease. In order to better understand congenital heart disease, we analyzed the human genetics of cardiac malformations. In particular, we studied heterotaxy patients with congenital heart disease for copy number variations. Heterotaxy is a disorder of left-right patterning and alters cardiac development due to failure of cardiac looping morphogenesis. In a heterotaxy patient, we identified duplication in the NUP188 gene, which encodes a component of the nuclear pore complex known as a nucleoporin. We then modeled this cardiovascular disease in Xenopus by knocking down nup188, which recapitulated the human heterotaxy phenotype. The main goal of this proposal is to analyze the role of nucleoporins in left-right patterning and congenital heart disease. Our preliminary data suggest that nucleoporins are important for cilia. Cilia are critical regulators of left-right patterning and so loss of cilia could explain the left-ight phenotype. In this proposal, we have three main aims: 1) Analyze multiple nucleoporins to see if they also alter left-right patterning and cilia 2) use super-resolution imaging to define the structure of nucleoporins at the base of the cilium and 3) determine the mechanism by which nucleoporins contribute to the function of cilia.