CRISPR/Cas9 and small molecules for targeting sperm function and fertilization
用于靶向精子功能和受精的 CRISPR/Cas9 和小分子
基本信息
- 批准号:9278440
- 负责人:
- 金额:$ 17.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acrosome ReactionAdverse effectsAmino AcidsAreaArmadillo RepeatCRISPR/Cas technologyCalcineurinCalcineurin inhibitorCatalytic DomainChimeric ProteinsCollaborationsContraceptive AgentsContraceptive methodsCyclosporineDefectDevelopmentEpididymisFK506FertilityFertilizationGene Transfer TechniquesGenesGerm CellsGoalsGrantHumanImmunosuppressive AgentsInfertilityIntegral Membrane ProteinKnock-inKnock-outLaboratoriesLeadMale Contraceptive AgentsMale InfertilityMembrane ProteinsMorphogenesisMorphologyMusMutant Strains MiceMutateMutationNational Institute of Child Health and Human DevelopmentOocytesPPP3CA genePPP3CC genePPP3R2 genePathway interactionsPharmaceutical PreparationsPharmacology StudyPhenocopyPhysiologicalPlanetsPolypeptide N-acetylgalactosaminyltransferasePopulationPopulation GrowthProcessProtein IsoformsProteinsPublishingResourcesScienceScientistSignaling ProteinSite-Directed MutagenesisSperm MidpieceSperm MotilitySperm TailSurfaceSystemTechnologyTestisTransgenic ModelWomanWorkcell motilitycell typecontraceptive targeteggflexibilityfolate-binding proteinfunctional genomicsin vivoinhibitor/antagonistmalemenmouse genomemouse modelnovelpre-clinicalpreventprofessorprotein functionreceptorreproductive functionscreeningsmall moleculesmall molecule inhibitorsperm cellsperm functionsperm proteinstructural biologysuccesstreatment duration
项目摘要
PROJECT 2 SUMMARY (CRISPR/Cas9 and small molecules for targeting sperm function and fertilization)
The overall goals of Project 2 are to use CRISPR/Cas9 to understand the formation of functional sperm
and identify small-molecule probes and preclinical candidates to target fertilization-required proteins
for a contraceptive effect in vivo. Population growth is a major worldwide issue, and our resources cannot
continue to sustain these population increases, and because of this, NICHD has made contraception a priority
focus area. Because our group is focused on the development of contraceptives that specifically target sperm
and fertilization, these germ cell-selective contraceptives would eliminate unwanted side effects. The Ikawa
laboratory has developed the CRISPR/Cas9 system to efficiently mutate genes in vivo including the Cetn1 and
Prm1 genes required for male fertility. In this P01, we will use CRISPR/Cas9 technology to advance our
understanding of fertility pathways in all three Projects and generate useful information to move these target
proteins and other related pathway proteins into the DEC-Tec Core for screening. For contraceptive targets in
Project 2, we will focus on two sperm-egg fusion transmembrane/signaling proteins and four sperm motility-
related proteins that we have shown are evolutionarily-conserved and required only for male fertility. The Ikawa
laboratory has effectively used the CRISPR/Cas9 system to generate mutations in over 200 mouse genes
including the genes described in this proposal. This strategy has also successfully produced knockin of tag
sequences into loci. We have used CRISPR/Cas9 independently and in collaboration with the Matzuk
laboratory (Project 1) to uncover proteins required for sperm-egg fusion and sperm motility. Functional analysis
of these mouse models will help not only to decipher the mechanisms by which these proteins function in
sperm-egg fusion and sperm motility but also to develop contraceptive drugs to target these essential
pathways. The screening of small molecules using the DEC-TEC Core will accelerate this process. Our overall
hypothesis is that CRISPR/Cas9 and DEC-Tec will help us to understand the network of interactions of these
proteins for sperm function, rapidly identify multiple small molecules that are directed at these essential
spermatogenic proteins, and create an assortment of contraceptives for men and women. The Specific Aims of
Project 2 are: 1) Manipulate the mouse genome and characterize the interrelationship of sperm-egg fusion
proteins; 2) Use CRISPR/Cas9 to study the mechanism of action of novel testis-specific proteins; and 3) Use
DEC-Tec to identify small-molecule drug-like probes and preclinical candidates to inhibit sperm motility-specific
and fertilization-specific proteins for a contraceptive effect in vivo. The success of Project 2 and this P01 grant
relies on the continued collaborations of Project 2 with Dr. Matzuk in Project 1, Drs. Sonnenburg, Lamb, and
Huang in Project 3, and the scientists in the DEC-Tec Core. Our goal is to develop multiple unique transgenic
models and non-hormonal contraceptives for mechanistic and pharmacologic studies in vivo in this P01 grant.
项目2概要(CRISPR/Cas9和小分子用于靶向精子功能和受精)
项目2的总体目标是使用CRISPR/Cas9来了解功能性精子的形成。
并确定小分子探针和临床前候选物,以靶向受精所需的蛋白质
体内避孕效果。人口增长是一个重大的世界性问题,我们的资源不能
继续维持这些人口增长,正因为如此,NICHD将避孕作为优先事项
重点领域。因为我们的小组专注于开发专门针对精子的避孕药
和受精,这些生殖细胞选择性避孕药将消除不必要的副作用。伊川
该实验室已经开发出CRISPR/Cas9系统,可以有效地在体内突变基因,包括Cetn 1和
雄性不育所需的prm 1基因。在本次P01中,我们将使用CRISPR/Cas9技术来推进我们的
了解所有三个项目的生育途径,并生成有用的信息,以推动这些目标
蛋白和其他相关途径蛋白进入DEC-Tec Core进行筛选。避孕目标
项目2,我们将专注于两个精卵融合跨膜/信号蛋白和四个精子运动-
我们已经证明的相关蛋白质是进化保守的,并且仅为男性生育力所需。伊川
一个实验室已经有效地使用CRISPR/Cas9系统在200多个小鼠基因中产生突变
包括这个提议中描述的基因。这一策略也成功地产生了敲入标签
序列转化为基因座。我们已经独立使用CRISPR/Cas9,并与Matzuk合作
实验室(项目1),以揭示精卵融合和精子活力所需的蛋白质。功能分析
这些小鼠模型不仅有助于破译这些蛋白质在体内发挥作用的机制,
精子-卵子融合和精子活力,而且还开发针对这些基本的避孕药物
途径。使用DEC-TEC Core筛选小分子将加速这一过程。我们的整体
假设CRISPR/Cas9和DEC-Tec将帮助我们了解这些基因的相互作用网络,
精子功能的蛋白质,快速识别多种小分子,这些小分子是针对这些基本的
生精蛋白,并创造了一个男性和女性避孕药品种。的具体目标
项目二是:1)小鼠基因组操作及精卵融合的相互关系研究
2)使用CRISPR/Cas9来研究新型睾丸特异性蛋白的作用机制;以及3)使用CRISPR/Cas9来研究新型睾丸特异性蛋白的作用机制。
DEC-Tec确定小分子药物样探针和临床前候选药物,以抑制精子运动特异性
和用于体内避孕作用的受精特异性蛋白质。项目2和P01赠款的成功
依赖于项目2与项目1中的Matzuk博士、Sonnenburg博士、Lamb博士和
黄在项目3,和科学家在DEC-Tec核心。我们的目标是开发多种独特的转基因
模型和非激素避孕药的机制和药理学研究在体内在这个P01补助金。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MASAHITO IKAWA其他文献
MASAHITO IKAWA的其他文献
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{{ truncateString('MASAHITO IKAWA', 18)}}的其他基金
CRISPR/Cas9 and small molecules for targeting sperm function and fertilization
用于靶向精子功能和受精的 CRISPR/Cas9 和小分子
- 批准号:
10164828 - 财政年份:2017
- 资助金额:
$ 17.61万 - 项目类别:
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