Discovery & Function of Fertilization-Specific Molecules

发现

• 批准号: 7565890
• 负责人: F. Kent Hamra
• 金额: $ 29.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565890
• 关键词: Acrosome Reaction; Adhesions; Behavior; Behavioral; Blast Cell; Breeding; Calcium Channel; Candidate Disease Gene; Cell physiology; Child; Chromosome Mapping; Complement; Complementary DNA; Complex; Contraceptive Agents; Contraceptive Usage; Coupled; Couples; Cyclic AMP; Data; Databases; Development; Domestic Animals; Event; Expressed Sequence Tags; Failure; Family; Fertility; Fertilization; Food; Foundations; Gene Expression; Gene Targeting; Genes; Germ Cells; Giant Cells; Goals; Health Benefit; Human; Hydrogen; Infertility; Intuition; Ions; Knowledge; Laboratories; Lectin; Libraries; Literature; Litter Size; Maps; Meiosis; Membrane Potentials; Messenger RNA; Methods; Modification; Molecular; Mutagenesis; Open Reading Frames; Pathway interactions; Peptide Signal Sequences; Phenotype; Play; Population; Principal Investigator; Process; Proteins; Receptor Gene; Regulation; Regulatory Pathway; Respondent; Role; Selection Criteria; Signaling Molecule; Sodium; Sodium-Hydrogen Antiporter; Source; Specificity; Sperm Motility; Surveys; System; Testis; Transcript; Tyrosine Phosphorylation; Wild Animals; aminophospholipid transporter; base; cell motility; chemokine; chemokine receptor; egg surface sperm receptor; male; mature animal; men; method development; mouse genome; programs; prototype; receptor; reproductive; research study; response; sperm analysis; sperm cell; sperm function; translocase

DESCRIPTION (provided by applicant): The human population continues to expand alarming rates making the development of safer, more economical and effective contraceptives an important health-related goal. In a 1997 survey by the Henry J. Kaiser Family Foundation, more than 66% of respondents believed that men should play a larger role in contraceptive use. The ability to intervene in fertilization could aid couples wanting children, increase reproductive efficiency in endangered species or domestic animals used as food sources, and decrease fertilization rates of certain wild animal populations such as vermin, benefiting the health of millions of people. However, the fertilization process remains poorly understood, leading to severe limitations in development of methods to intervene. The over-all goal of this project is to identify genes critical to sperm behavior and fertilization. The criterion for initial selection of genes relies on cDNA sequences encoding proteins that predict a sperm receptor, channel, transporter, adhesion protein, translocase or ion exchanger, and on genes expressed exclusively in spermatozoa during or after meiosis. Specific Aim 1 centers on the discovery and functional analysis of new sperm candidate genes (lectin-like, single TM potential receptor, chemokine-like tetraspan). They will be targeted for disruption to determine the effects on sperm behavior and fertility. The gene products will be studied to define mechanisms of regulation. Searches will continue for new candidate genes critical to fertility, and the role of a sperm-specific sodium/hydrogen exchanger (sNHE) in capacitation and induction of the acrosome reaction will be delineated. Specific Aim 2 is a detailed analysis of candidate gene product regulation. The sNHE will serve as the primary prototype for other candidate gene products. Studies will concentrate on mechanisms of regulation of the sNHE (e.g. the effects of covalent modification and associated proteins on sNHE activity). Based on these studies, linkage maps will begin to connect pathways from the sNHE, or other candidate gene products, to sperm behavioral responses such as motility activation or induction of the acrosome reaction.

描述(申请人提供)：人类人口继续以惊人的速度增长，使开发更安全、更经济和更有效的避孕药具成为与健康有关的重要目标。在1997年亨利·J·凯泽家庭基金会的一项调查中，超过66%的受访者认为男性应该在避孕措施的使用中发挥更大的作用。干预受精的能力可以帮助想要孩子的夫妇，提高濒危物种或用作食物来源的家畜的繁殖效率，并降低某些野生动物种群的受精率，如害虫，从而有利于数百万人的健康。然而，受精过程仍然知之甚少，导致干预方法的开发受到严重限制。这个项目的总体目标是识别对精子行为和受精至关重要的基因。基因初始选择的标准依赖于编码蛋白质的cdna序列，这些蛋白质预测精子受体、通道、转运体、黏附蛋白、转位酶或离子交换器，以及精子在减数分裂过程中或减数分裂后独有表达的基因。具体目标1集中于新的精子候选基因的发现和功能分析(凝集素样单TM潜在受体、趋化素样Tetraspan)。他们将被作为干扰的目标，以确定对精子行为和生育能力的影响。将对基因产物进行研究，以确定调控机制。将继续寻找对生育能力至关重要的新候选基因，并将描述精子特异性钠/氢交换器(SNHE)在获能和诱导顶体反应中的作用。具体目标2是对候选基因产物调控的详细分析。SNHE将作为其他候选基因产品的主要原型。研究将集中在sNHE的调节机制(例如，共价修饰和相关蛋白对sNHE活性的影响)。在这些研究的基础上，连锁图谱将开始连接从sNHE或其他候选基因产物到精子行为反应的途径，如运动激活或诱导顶体反应。

项目成果

A novel aminophospholipid transporter exclusively expressed in spermatozoa is required for membrane lipid asymmetry and normal fertilization.

• DOI: 10.1016/j.ydbio.2003.11.004
• 发表时间: 2004-03
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Lei Wang;Crystal Beserra;D. Garbers

Generating knockout rats by transposon mutagenesis in spermatogonial stem cells.

• DOI: 10.1038/nmeth.1461
• 发表时间: 2010-06
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Izsvak, Zsuzsanna;Froehlich, Janine;Grabundzija, Ivana;Shirley, James R.;Powell, Heather M.;Chapman, Karen M.;Ivics, Zoltan;Hamra, F. Kent
• 通讯作者: Hamra, F. Kent