Regulation and functions of male-derived shed microvesicles in Drosophila reproduction

果蝇繁殖中雄性脱落微泡的调节和功能

基本信息

  • 批准号:
    BB/L007096/1
  • 负责人:
  • 金额:
    $ 60.82万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2014
  • 资助国家:
    英国
  • 起止时间:
    2014 至 无数据
  • 项目状态:
    已结题

项目摘要

Although males and females share a common goal when they mate, the production of offspring who carry copies of their genes, there is at the same time an important conflict between them. While on the one hand, males of many species can best maintain their gene pool by mating with many females and preventing other males from competing, females are often best served by sampling sperm from multiple males. Three years ago, we started to study the ways in which males have adapted to fight this battle of the sexes. We speculated that males had developed specialised ways of delivering signals to females that made their sperm work at their best and also stopped other males from mating with these females. We decided to work with the fruit fly, partly because it was already known that male flies had developed ingenious ways to fight the reproductive battle. They assemble a plug in the female uterus that blocks remating and also alter female behaviour so she rejects subsequent advances from other males. Flies are ideal for studies of this kind because they can be easily manipulated to identify the genes involved and find out how they work. About 70% of all genes known to be involved in human disease are also found in flies. Lots of the basic mechanisms in human biology were originally studied in flies or other simple organisms before being looked at in humans. We are studying a male gland in flies called the accessory gland that seems to share many features of the human prostate and seminal vesicles, which generate most of the main components of semen. We have already shown that one type of cell in this gland secretes tiny membrane-bound packages that are passed into females on mating and fuse to sperm. These packages, called exosomes, are required to alter female behaviour after mating. Remarkably the human prostate also produces exosomes that fuse to sperm. Our work is starting to reveal how these exosomes are made and how they affect sperm, and we are beginning to see how defects in exosome production might be involved in aspects of prostate cancer, ideas that we are now following up with clinical colleagues.Recently we discovered that another type of cell in the accessory gland secretes larger membrane-bound structures called shed microvesicles (SMVs) that are also passed to females in huge numbers during mating. These vesicles carry several key proteins that are already known to drive changes in the female after mating, like increased egg laying, sperm storage, mating plug formation and altered remating behaviour. SMVs coalesce to make a mating plug in one part of the female reproductive tract, while in other parts, they remain intact, but release one of their attached proteins, which then binds to sperm and allows it to be stored. These SMVs may also bind to female cells, raising the possibility that they could communicate to females in this way.Several important fly molecules involved in this process are related to mammalian reproductive proteins. In fact, the discovery of SMVs in fly semen explains a mystery in both fly and mammalian reproduction - several proteins secreted into semen look like they should be attached to membranes, and not secreted. We will study how SMVs are made, work out what they do in females after mating and how these events are controlled by proteins made in the accessory gland. This work will not only help us to understand fundamental principles of reproduction, it may give us new ideas for reproductive therapies and contraception. SMVs are also important in blood clotting, inflammation and growth. We have evidence that the basic controls on these different processes are similar, opening up the possibility that our work will provide new insights into diseases where these processes go wrong. Our proposed work, looking into an important, but previously intractable problem, may therefore impact on several areas of biology relevant to human health.
尽管雄性和雌性在交配时有着共同的目标,即产生携带其基因副本的后代,但它们之间同时也存在着重要的冲突。一方面,许多物种的雄性可以通过与许多雌性交配并阻止其他雄性竞争来最好地维持其基因库,而雌性通常最好通过从多个雄性身上采集精子来获得服务。三年前,我们开始研究男性如何适应这场性别之战。我们推测,雄性已经开发出专门的方式向雌性传递信号,使它们的精子发挥最佳作用,并阻止其他雄性与这些雌性交配。我们决定用果蝇进行研究,部分原因是众所周知,雄性果蝇已经发展出巧妙的方法来对抗生殖之战。它们在雌性子宫中安装一个塞子,阻止再交配,并改变雌性的行为,以便她拒绝其他雄性的后续求爱。果蝇是此类研究的理想选择,因为可以轻松操纵它们来识别相关基因并了解它们的工作原理。已知与人类疾病有关的所有基因中,约 70% 也在果蝇中发现。人类生物学的许多基本机制最初是在果蝇或其他简单生物体中研究的,然后才在人类身上进行研究。我们正在研究果蝇的一种雄性腺体,称为副腺体,它似乎具有人类前列腺和精囊的许多特征,而精液的大部分主要成分都是由精囊产生的。我们已经证明,该腺体中的一种细胞会分泌微小的膜结合包,这些包在交配时传递到雌性体内并与精子融合。这些被称为外泌体的包裹是改变雌性交配后行为所必需的。值得注意的是,人类前列腺也会产生与精子融合的外泌体。我们的工作开始揭示这些外泌体是如何产生的以及它们如何影响精子,并且我们开始了解外泌体产生的缺陷如何可能与前列腺癌的各个方面有关,我们现在正在与临床同事一起跟进这些想法。发现附属腺中的另一种细胞会分泌更大的膜结合结构,称为脱落微泡(SMV),这些结构在交配过程中也会大量传递给雌性。这些囊泡携带几种关键蛋白质,已知这些蛋白质会在交配后驱动雌性发生变化,例如产卵量增加、精子储存、交配栓形成和重新交配行为改变。 SMV 在女性生殖道的一部分结合形成交配塞,而在其他部分,它们保持完整,但释放其附着的一种蛋白质,然后与精子结合并允许其储存。这些 SMV 也可能与雌性细胞结合,从而提高了它们以这种方式与雌性进行交流的可能性。参与这一过程的几个重要的果蝇分子与哺乳动物的生殖蛋白有关。事实上,果蝇精液中 SMV 的发现解释了果蝇和哺乳动物繁殖中的一个谜团——分泌到精液中的几种蛋白质看起来应该附着在膜上,而不是分泌出来。我们将研究 SMV 是如何产生的,弄清楚它们在交配后对雌性的作用,以及这些事件是如何由附属腺中产生的蛋白质控制的。这项工作不仅有助于我们了解生殖的基本原理,还可能为我们提供生殖治疗和避孕的新思路。 SMV 在血液凝固、炎症和生长中也很重要。我们有证据表明,这些不同过程的基本控制是相似的,这开启了我们的工作将为这些过程出错的疾病提供新见解的可能性。因此,我们提出的工作旨在研究一个重要但以前棘手的问题,可能会影响与人类健康相关的几个生物学领域。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
mTORC1 signalling mediates PI3K-dependent large lipid droplet accumulation in Drosophila ovarian nurse cells.
mTORC1 信号介导果蝇卵巢护理细胞中 PI3K 依赖性大脂滴积累。
  • DOI:
    http://dx.10.1242/bio.022210
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Mensah LB
  • 通讯作者:
    Mensah LB
Regulation of Dense-Core Granule Replenishment by Autocrine BMP Signalling in Drosophila Secondary Cells.
果蝇次级细胞中自分泌 BMP 信号传导对致密核心颗粒补充的调节。
  • DOI:
    http://dx.10.1371/journal.pgen.1006366
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Redhai S
  • 通讯作者:
    Redhai S
PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer.
PAT4 水平控制高尔基体中雷帕霉素耐药性 mTORC1 的氨基酸敏感性,并影响结直肠癌的临床结果。
  • DOI:
    http://dx.10.1038/onc.2015.363
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Fan SJ
  • 通讯作者:
    Fan SJ
Mating Induces Switch From Hormone-Dependent to - Independent Steroid Receptor-Mediated Growth in Drosophila Prostate-Like Cells
交配诱导果蝇前列腺样细胞从激素依赖性生长转变为非类固醇受体介导的生长
  • DOI:
    http://dx.10.1101/533976
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Leiblich A
  • 通讯作者:
    Leiblich A
Exosomal miRNAs as cancer biomarkers and therapeutic targets.
外泌体 miRNA 作为癌症生物标志物和治疗靶点。
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Clive Wilson其他文献

Glutamine Deprivation Regulates the Origin and Function of Cancer Cell Exosomes
谷氨酰胺剥夺调节癌细胞外泌体的起源和功能
  • DOI:
    10.1101/859447
  • 发表时间:
    2019-12-02
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shih‐Jung Fan;Benjamin Kroeger;Pauline P Marie;E. Bridges;John D. Mason;K. McCormick;C. Zois;H. Sheldon;N. K. Alham;Errin Johnson;M. Ellis;M. I. Stefana;C. Mendes;S. Wainwright;C. Cunningham;F. Hamdy;J. Morris;A. Harris;Clive Wilson;D. Goberdhan
  • 通讯作者:
    D. Goberdhan
P-element-mediated enhancer detection: a versatile method to study development in Drosophila.
P 元件介导的增强子检测:研究果蝇发育的通用方法。
  • DOI:
    10.1101/gad.3.9.1288
  • 发表时间:
    1989-09-01
  • 期刊:
  • 影响因子:
    10.5
  • 作者:
    H. Bellen;C. O’Kane;Clive Wilson;U. Grossniklaus;Rebecca Kurth Pearson;W. Gehring
  • 通讯作者:
    W. Gehring
Cytoplasmic activated protein kinase Akt regulates lipid-droplet accumulation in Drosophila nurse cells
细胞质激活蛋白激酶 Akt 调节果蝇护士细胞中脂滴的积累
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    N. Vereshchagina;Clive Wilson
  • 通讯作者:
    Clive Wilson
Mating Induces Switch From Hormone-Dependent to – Independent Steroid Receptor-Mediated Growth in Drosophila Prostate-Like Cells
交配诱导果蝇前列腺样细胞从激素依赖性生长转变为非类固醇受体介导的生长
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. Leiblich;Josephine E E U Hellberg;Aashika Sekar;C. Gandy;Siamak Redhai;M. Wainwright;Pauline P Marie;D. Goberdhan;F. Hamdy;Clive Wilson
  • 通讯作者:
    Clive Wilson
Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot
mTORC1 的氨基酸传感:细胞内转运蛋白是亮点
  • DOI:
    10.1016/j.cmet.2016.03.013
  • 发表时间:
    2016-04-12
  • 期刊:
  • 影响因子:
    29
  • 作者:
    D. Goberdhan;Clive Wilson;A. Harris
  • 通讯作者:
    A. Harris

Clive Wilson的其他文献

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{{ truncateString('Clive Wilson', 18)}}的其他基金

Sex Peptide-dependent microcarrier signalling in reproduction
生殖中性肽依赖性微载体信号传导
  • 批准号:
    BB/W015455/1
  • 财政年份:
    2022
  • 资助金额:
    $ 60.82万
  • 项目类别:
    Research Grant
Regulation and activities of amyloidogenic proteins APP and TGFBI in physiological and pathological protein aggregation
淀粉样蛋白APP和TGFBI在生理和病理蛋白聚集中的调节和活性
  • 批准号:
    BB/W00707X/1
  • 财政年份:
    2022
  • 资助金额:
    $ 60.82万
  • 项目类别:
    Research Grant
Regulation of exosome heterogeneity and function
外泌体异质性和功能的调节
  • 批准号:
    BB/R004862/1
  • 财政年份:
    2018
  • 资助金额:
    $ 60.82万
  • 项目类别:
    Research Grant
Linking reproductive behaviour and dense core granule biogenesis in secondary cells of the Drosophila male reproductive system
将果蝇雄性生殖系统次生细胞的生殖行为与致密核心颗粒生物发生联系起来
  • 批准号:
    BB/N016300/1
  • 财政年份:
    2016
  • 资助金额:
    $ 60.82万
  • 项目类别:
    Research Grant
Exosome signalling and cellular reprogramming in the Drosophila reproductive system
果蝇生殖系统中的外泌体信号传导和细胞重编程
  • 批准号:
    BB/K017462/1
  • 财政年份:
    2013
  • 资助金额:
    $ 60.82万
  • 项目类别:
    Research Grant

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The impact of a neonicotinoid pesticide on neural functions underlying learning and memory
新烟碱类农药对学习和记忆神经功能的影响
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研究对配子发生至关重要的 RNA 结合蛋白的分子功能和机制
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运动引起的压力恢复能力的性别和循环特定决定因素
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