Impact of 3' untranslated region sequence variants in spermiogenic gene expression and infertility
3非翻译区序列变异对精子发生基因表达和不育的影响
基本信息
- 批准号:10615700
- 负责人:
- 金额:$ 54.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAffectAllelesBioinformaticsBiological AssayCell Culture TechniquesCell LineCellsChromatinClinicalComplexConserved SequenceDataData SetDefectDeveloped CountriesDevelopmentEjaculationElementsEpigenetic ProcessExhibitsFertilityGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomeHaploidyHealthHumanIn VitroIndividualInfertilityLengthLesionMale InfertilityMastigophoraMeasuresMessenger RNAModelingMolecularMorphologyMusMutationNatureOrganismPathogenicityPatientsPhenotypePhylogenyPlayPoly APolyadenylationPopulationPost-Transcriptional RNA ProcessingPost-Transcriptional RegulationProcessProtein IsoformsProteinsRNARNA StabilityRegulationRegulatory ElementReporterReporter GenesRibosomesRoleSeminal fluidSingle Nucleotide PolymorphismSiteSourceSpecific qualifier valueSperm Count ProcedureSpermatidsSpermatocytesSpermatogenesisSpermiogenesisSystemTestingTestisTranscriptTranslationsUnited StatesUntranslated RNAVariantWild Type Mouseasthenospermiabasecandidate identificationcell motilityexomeexperimental studyfitnessgenetic regulatory proteinmRNA StabilitymRNA Translationmammalian genomemenmouse modelparticleposttranscriptionalrecruitreproductivescreeningsegregationsperm cellsperm functionsperm morphologytraffickingtranscriptome sequencingtranslational impactwhole genome
项目摘要
Male infertility is well-recognized as a major health problem in the United States. Clinically, the major cause is
poor semen quality, that is, oligozoospermia, asthenozoospermia, and/or teratozoospermia. About half of
infertility cases are thought to be genetic in nature, although the molecular bases are mostly unknown.
Remarkably, these sperm defects are not limited to infertile men; ~2% of all men exhibit suboptimal sperm
parameters, and the sperm counts among men in many developed countries have more than halved in the
past 40 years. Again, the underlying causes are unknown. Thus, it is a priority to understand the molecular
basis of these disturbing increases in reproductive problems in men. With respect to genetic and epigenetic
contributions to infertility, there are many stages and molecular processes that can be affected, including all
stages of spermatogenesis, and roles for thousands of genes required for fertility. This project focuses on post-
transcriptional gene regulation during spermiogenesis, the elaborate process by which round haploid
spermatids undergo dramatic morphological development to become mature, flagellated spermatozoa with a
highly compacted, inert genome. Post-transcriptional gene regulation plays a substantial role in
spermiogenesis. The 3′UTR (3′ untranslated region) is central in this respect, affecting mRNA stability,
translation and localization by influencing polyadenylation, access to regulatory proteins and noncoding RNAs,
and loading onto ribosomes or ribonuclear protein particles (RNPs). This project seeks to understand if and
how variation/mutation in the 3′UTRs of infertility patients plays a role in haploid gene expression and infertility.
Aim I will determine if there are systematic or specific alterations in the post-transcriptional regulatory function
of 3′UTRs in fertile versus infertile men, using 3′RNA-seq of round spermatids purified from ejaculates, and
public genome sequence data. Based on these data, we will identify and prioritize variants that reside within
motifs predicted bioinformatically to impact mRNA stability or other relevant attributes, focusing on genes
implicated in spermiogenesis. In Aim II, candidate variants will be screened via a high-throughput in vitro
system to identify those that indeed have an impact on mRNA stability and/or translation. Finally, Aim III will
create mouse models of these putative pathogenic variants, and assess molecular and phenotypic effects
upon reproductive parameters such as sperm number, morphology, motility, and fertility. Overall, if successful,
this will be the largest effort to date to identify genetic lesions that cause infertility via disruption of post-
transcriptional gene expression.
男性不育症是公认的主要健康问题在美国。临床上,主要原因是
精液质量差,即少精子症、弱精子症和/或畸形精子症。的一半左右
不孕症被认为是遗传性的,尽管分子基础大多是未知的。
值得注意的是,这些精子缺陷并不局限于不育男性;约2%的男性表现出次优精子
许多发达国家的男性精子数量在2008年减少了一半以上,
过去40年。同样,根本原因不明。因此,了解分子生物学是一个优先事项。
这些令人不安的男性生殖问题增加的基础。关于遗传和表观遗传
不孕症的贡献,有许多阶段和分子过程,可以受到影响,包括所有
精子发生的各个阶段,以及生育所需的数千个基因的作用。该项目的重点是后-
精子发生过程中的转录基因调控,圆形单倍体
精子细胞经历戏剧性的形态发育,成为成熟的,有鞭毛的精子,
高度紧凑的惰性基因组转录后基因调控在人类基因组中起着重要的作用。
精子发生3′UTR(3′非翻译区)在这方面是中心,影响mRNA的稳定性,
通过影响多聚腺苷酸化,进入调节蛋白和非编码RNA,
并装载到核糖体或核糖核蛋白颗粒(RNP)上。该项目旨在了解如果和
不育患者3′ UTR的变异/突变如何在单倍体基因表达和不育中发挥作用。
目的确定转录后调节功能是否存在系统性或特异性改变
使用从精液中纯化的圆形精子细胞的3′RNA-seq,
公共基因组序列数据。基于这些数据,我们将识别并优先考虑存在于
生物信息学预测的影响mRNA稳定性或其他相关属性的基序,侧重于基因
与精子生成有关在Aim II中,候选变体将通过高通量体外
系统来鉴定那些确实对mRNA稳定性和/或翻译有影响的基因。最后,Aim III将
创建这些假定致病变异的小鼠模型,并评估分子和表型效应
对生殖参数如精子数量、形态、活力和生育力的影响。总的来说,如果成功,
这将是迄今为止最大的努力,以确定遗传病变,导致不孕症,通过破坏后,
转录基因表达
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ANDREW W GRIMSON其他文献
ANDREW W GRIMSON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ANDREW W GRIMSON', 18)}}的其他基金
MicroRNAs in Tissue-resident memory T cells
组织驻留记忆 T 细胞中的 MicroRNA
- 批准号:
10609026 - 财政年份:2022
- 资助金额:
$ 54.31万 - 项目类别:
MicroRNAs in Tissue-resident memory T cells
组织驻留记忆 T 细胞中的 MicroRNA
- 批准号:
10354926 - 财政年份:2022
- 资助金额:
$ 54.31万 - 项目类别:
Impact of 3' untranslated region sequence variants in spermiogenic gene expression and infertility
3非翻译区序列变异对精子发生基因表达和不育的影响
- 批准号:
10157201 - 财政年份:2021
- 资助金额:
$ 54.31万 - 项目类别:
Impact of 3' untranslated region sequence variants in spermiogenic gene expression and infertility
3非翻译区序列变异对精子发生基因表达和不育的影响
- 批准号:
10398877 - 财政年份:2021
- 资助金额:
$ 54.31万 - 项目类别:
A Single Comprehensive Assay for Gene Regulatory Profiling Optimized for Minimal Sample Input Requirements
针对最小样本输入要求进行优化的基因调控分析的单一综合分析
- 批准号:
10398158 - 财政年份:2020
- 资助金额:
$ 54.31万 - 项目类别:
Establishing Methods to Delineate 3'UTR-mediated Regulation
建立描述 3UTR 介导调节的方法
- 批准号:
10316261 - 财政年份:2020
- 资助金额:
$ 54.31万 - 项目类别:
A Single Comprehensive Assay for Gene Regulatory Profiling Optimized for Minimal Sample Input Requirements
针对最小样本输入要求进行优化的基因调控分析的单一综合分析
- 批准号:
10159213 - 财政年份:2020
- 资助金额:
$ 54.31万 - 项目类别:
A Single Comprehensive Assay for Gene Regulatory Profiling Optimized for Minimal Sample Input Requirements
针对最小样本输入要求进行优化的基因调控分析的单一综合分析
- 批准号:
10618150 - 财政年份:2020
- 资助金额:
$ 54.31万 - 项目类别:
Roles for DevelopmentallyRegulated microRNAs in Neonatal Immunity
发育调控的 microRNA 在新生儿免疫中的作用
- 批准号:
10221489 - 财政年份:2017
- 资助金额:
$ 54.31万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 54.31万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 54.31万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 54.31万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 54.31万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 54.31万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 54.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 54.31万 - 项目类别: