权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Developmental models to determine the molecular mechanisms that cause MYH9-related diseases

确定导致 MYH9 相关疾病的分子机制的发育模型

基本信息

批准号：
9894984
负责人：
Jennifer H Gutzman
金额：
$ 7.6万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894984
关键词：
Abnormal Platelet Affect Biological Assay Biological Models Biological Process CRISPR/Cas technology Cell Shape Cell division Cells Characteristics Clinical Codon Nucleotides Complex Data Defect Development Disease Ear Embryo Epstein&apos s syndrome Etiology Eye Future Generations Genes Goals Human Image Investigation Kidney Knowledge Label Laboratories Lead Mission Modeling Molecular Mutate Mutation National Institute of Child Health and Human Development Nephritis Nonmuscle Myosin Type IIA Optics Organ Otic Vesicle Outcome Patients Population Proteins Public Health Research Resolution Role Structure Symptoms Syndrome System Techniques Testing Time Tissues Transgenic Organisms Vertebrates Visual Work Zebrafish cell motility deafness disability burden ear development experience genome editing hearing impairment in vivo innovation insight model development mutant non-muscle myosin novel organ growth tool transmission process

项目摘要

This proposal aims to develop vertebrate models to elucidate molecular mechanisms by which known mutations in MYH9 disrupt development. There are five diseases that result from mutations in MYH9, including clinical syndromic disorders that are classified as MYH9-related diseases: May-Hegglin anomaly, Sebastian, Fetchner, and Epstein syndrome; and non-syndromic deafness DFNA17. These diseases share common mutations in the MYH9 gene and are characterized by a number of symptoms including platelet abnormalities, nephritis, visual defects, and hearing loss. MYH9 encodes for the highly conserved non-muscle myosin IIA protein (NMIIA), which has essential roles in cell division, cell migration, and cell shape changes. However, there is a critical gap in the understanding of how MYH9 mutations found in the human population contribute to the etiology of MYH9-related diseases. We propose to generate zebrafish (Danio rerio) models of the most common MYH9 mutations to examine the development of the organs that are affected in MYH9-related disease, particularly the ear, eye, and kidney. Zebrafish models will provide distinct advantages over current mammalian models in the ability to access and examine early organ development at single-cell resolution using live imaging. Zebrafish embryos are optically transparent, have rapid development, and genome editing techniques in zebrafish are well established. Our long-term research goal is to determine the molecular mechanisms for how mutations in the MYH9 gene lead to MYH9-related diseases. As the first step towards our long-term research goal, the overall objective of this R03 proposal is to establish zebrafish models and transgenic lines to study the mechanisms that cause MYH9-related diseases. Our central hypothesis is that zebrafish models of conserved MYH9 mutations and NMIIA-labeled transgenic lines can be generated and will allow us to elucidate the molecular mechanisms that cause MYH9-related diseases. We will test our central hypothesis by pursuing the following specific aims. Aim 1 is to generate myh9 mutant zebrafish lines with targeted and specific mutations that correspond to the most common human mutations in MYH9-related diseases. Aim 2 is to create transgenic zebrafish lines with endogenously labelled NMIIA protein to examine NMIIA localization and dynamics during development. We will accomplish these aims by generating zebrafish models of MYH9 mutations using CRISPR/Cas9 genome editing. The proposed work is innovative and significant because these studies will establish developmental vertebrate models that are needed to investigate and identify the role for mutations in the highly conserved MYH9 gene and determine the molecular mechanisms for how these mutations cause MYH9-related diseases. The outcomes from this proposal are expected to have an important positive impact because they will provide the tools necessary to define how mutations in MYH9 lead to developmental defects.

本研究旨在建立脊椎动物模型，以阐明已知的分子机制