Genetic Modifier Activity and Network Properties of Nxf1

Nxf1 的遗传修饰活性和网络特性

基本信息

批准号：
8045522
负责人：
BRUCE A HAMILTON
金额：
$ 33.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8045522
关键词：
Affect Affinity Alleles Alternative Splicing Amino Acid Substitution Animal Disease Models Animal Model Animals Architecture Attenuated Award Behavioral Biological Assay CAST1 Protein Cell Culture Techniques Cells Communicable Diseases Computer Architectures DNA Sequence Development Diptera Disease Disease model Disease susceptibility Drosophila genus Endogenous Retroviruses Feedback Gene Expression Gene Targeting Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Suppression Genotype Hereditary Disease Heterozygote Homologous Gene Human Genetics In Vitro Injection of therapeutic agent Insertion Mutation Introns Laboratory mice Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Mutation Natural Immunity Nuclear Export Orthologous Gene Outcome Parasites Pathway interactions Period Analysis Phenotype Population Positioning Attribute Predisposition Process Property Proteins Protocols documentation RNA RNA Binding RNA Processing RNA Sequences RNA Viruses Regulation Resistance Retrotransposon Role Secondary to Site Testing Transcript Variant Work base crosslink design disease phenotype embryonic stem cell fungus genetic analysis genome-wide human disease in vivo insight loss of function mRNA Precursor molecular phenotype mouse model mutant novel pathogen positional cloning pressure programs public health relevance research study trait

项目摘要

DESCRIPTION (provided by applicant): Most human disease has a genetic basis in cause, susceptibility, or resistance. However, the genetic architectures for most disease phenotypes are only poorly understood and architectures of genetic plasticity - the ability to modify genetic networks to favor one trait without adversely affecting other traits that rely on the same underlying genes - are understood almost not at all. We have previously demonstrated through positional identification of a novel wild-derived modifier gene in mice one instructive example. The Mvb1 locus attenuates the effects of retroviral insertion mutations without apparent disruption of the host gene expression program. Indeed, the variant we identified shows hallmarks of positive selection in wild populations, consistent with a role in innate immunity to a pathogen. This competing renewal application continues our work to understand the mechanisms of genetic suppression mediated by alleles of the Nxf1 gene at the Mvb1 locus. This renewal supports development of new mouse models for human disease and therapy based on modulating gene expression levels to reflect therapies that increase or replace expression of genetic defects, analysis of the genetic networks of normal gene expression that might be affected by manipulating this pathway, and tests for effects of feedback regulation within the proposed network architecture. PUBLIC HEALTH RELEVANCE: Understanding mechanisms through which gene expression networks have been modified by selective pressures or can be manipulated therapeutically to favor host gene expression programs over those of pathogens, including RNA viruses, and molecular parasites, including retrotransposons, has potential applications in infectious disease and cancer. Understanding the network architecture and properties of component proteins such as Nxf1 has applications for animal models of a wide range of genetic disease and genetic susceptibility to disease as well as providing new insight into basic mechanisms of RNA processing downstream of transcriptional initiation.

描述（由申请人提供）：大多数人类疾病在原因，易感性或抗性方面具有遗传基础。但是，大多数疾病表型的遗传体系结构仅是对遗传可塑性的理解不足和遗传可塑性的结构 - 这种能力修改遗传网络以偏爱一种性状而不会不利影响依赖相同基本基因的其他特征的能力 - 几乎完全不了解。我们先前曾通过对小鼠中新型野生衍生的修饰基因基因的位置鉴定来证明一个启发性的例子。 MVB1基因座减弱了逆转录病毒插入突变的影响，而不会明显破坏宿主基因表达程序。实际上，我们确定的变体显示了野生种群中阳性选择的标志，这与对病原体的先天免疫发挥作用一致。这种竞争性更新应用继续我们的工作，以了解由MVB1基因座NXF1基因等位基因介导的遗传抑制机制。这种更新支持基于调节基因表达水平的新小鼠模型的新小鼠模型，以反映疗法，以增加或替换遗传缺陷的表达，分析可能通过操纵该途径来影响正常基因表达的遗传网络，并测试提议网络内反馈调节的影响。公共卫生相关性：理解基因表达网络已通过选择性压力改变的机制，或者可以通过治疗方法进行操纵，以偏爱宿主基因表达程序，而不是病原体（包括RNA病毒）和包括RNA病毒的病原体和包括逆转录转座子在内的分子寄生虫，在感染疾病和癌症中具有潜在的应用。了解组件蛋白（例如NXF1）的网络结构和性质具有广泛遗传疾病和遗传易感性的动物模型的应用，并为转录起始下游RNA处理的基本机制提供了新的见解。