Defining the Biological Functions of Novel Lipids in Healthy and Wounded Skin

定义新型脂质在健康和受伤皮肤中的生物学功能

基本信息

  • 批准号:
    MR/M011445/1
  • 负责人:
  • 金额:
    $ 104.77万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2015
  • 资助国家:
    英国
  • 起止时间:
    2015 至 无数据
  • 项目状态:
    已结题

项目摘要

Healthy skin forms a barrier that is essential for preventing infection and loss of water from our bodies. Loss of this barrier occurs during common skin diseases such as psoriasis and eczema, and allows infection during chronic wounds. Lipids (fats) are required to maintain the barrier, but little is known regarding how they do this, with the role of skin lipids in disease a major under-researched area. In Cardiff and Vanderbilt, we discovered several families of lipids that are generated by skin or by blood cells that migrate to the skin during response to injury, or in skin disease. Our preliminary data suggests that several of these may be important in maintaining the health of skin and preventing disease. They are made by a family of proteins (enzymes) called lipoxygenases (LOXs) and include two types of lipids, called phospholipids and ceramides. In this study we will use a number of approaches to determine the roles of the lipids in regulating skin biology. The studies may lead to development of new treatments for common skin disorders and chronic wounds, conditions that cause significant morbidity in a large section of our population. The primary objective of this study is to determine how lipids discovered by the Cardiff and Vanderbilt groups regulate skin biology. To do this we will use reconstituted human skin, mouse models and patient samples.Aims: (1) Determine the structure and localization of the lipids in human skin. In this aim we will determine the structures of all the lipids still to be fully characterized. We will also use imaging and other methods to determine where the lipids are located in skin (which layers of the epidermis). Both healthy skin and samples from patients with inflammatory skin disorders will be studied. (2) Determine how the lipids regulate skin health and disease at the molecular level. We propose that the lipids may help regulate skin through two different molecular processes. These include regulation of an important protein called PPAR and through regulating how blood cells that have migrated into the skin behave during health and disease. We will study these events using a 3D cultured human skin system, and in a murine model of wounding in vivo. (3) Characterise regulation of skin gene expression by LOX-derived lipids. To identify pathways by which the lipids regulate skin health, the enzymes that generate them will be removed in cultured human skin using an approach called siRNA. A global screening approaches called RNAseq will then determine changes in gene expression in specific skin compartments and how these are mediated. (4) Discover new lipids formed in skin disease. The total number and types of lipids are present in skin is unknown. As part of a European Research Council grant, we are developing new methods for studying lipids that will be applied to our studies of skin lipids in this project. Lipids will be catalogued in samples of healthy skin, and in biopsies from patients with the common skin disorders, psoriasis and eczema, with a view to identifying new lipids that regulate skin health and disease. These studies will determine how lipids regulate skin biology, and may lead to design of new therapies for inflammatory skin diseases and wounds.
健康的皮肤形成屏障,对于防止感染和身体水分流失至关重要。这种屏障的丧失会在牛皮癣和湿疹等常见皮肤病中发生,并导致慢性伤口感染。维持屏障需要脂质(脂肪),但人们对其如何做到这一点知之甚少,皮肤脂质在疾病中的作用是一个主要的研究不足的领域。在卡迪夫和范德比尔特,我们发现了几个由皮肤或血细胞产生的脂质家族,这些脂质在受伤或皮肤病反应期间迁移到皮肤。我们的初步数据表明,其中一些可能对维持皮肤健康和预防疾病很重要。它们由称为脂氧合酶 (LOX) 的蛋白质(酶)家族制成,并包含两种类型的脂质,称为磷脂和神经酰胺。在这项研究中,我们将使用多种方法来确定脂质在调节皮肤生物学中的作用。这些研究可能会导致针对常见皮肤病和慢性伤口的新疗法的开发,这些疾病在我们大部分人口中造成显着的发病率。这项研究的主要目的是确定卡迪夫和范德比尔特研究小组发现的脂质如何调节皮肤生物学。为此,我们将使用重建的人体皮肤、小鼠模型和患者样本。目的:(1)确定人体皮肤中脂质的结构和定位。为此,我们将确定所有尚未完全表征的脂质的结构。我们还将使用成像和其他方法来确定脂质在皮肤中的位置(表皮的哪一层)。将研究健康皮肤和炎症性皮肤病患者的样本。 (2)确定脂质如何在分子水平上调节皮肤健康和疾病。我们认为脂质可能通过两种不同的分子过程帮助调节皮肤。其中包括调节一种名为 PPAR 的重要蛋白质,以及调节迁移到皮肤的血细胞在健康和疾病期间的行为。我们将使用 3D 培养的人类皮肤系统和小鼠体内受伤模型来研究这些事件。 (3) 表征 LOX 衍生脂质对皮肤基因表达的调节。为了确定脂质调节皮肤健康的途径,将使用一种称为 siRNA 的方法去除培养的人体皮肤中产生脂质的酶。然后,一种称为 RNAseq 的全球筛查方法将确定特定皮肤区室中基因表达的变化以及这些变化是如何介导的。 (4)发现皮肤病中形成的新脂质。皮肤中存在的脂质的总数和类型尚不清楚。作为欧洲研究委员会拨款的一部分,我们正在开发研究脂质的新方法,这些方法将应用于我们本项目中的皮肤脂质研究。将对健康皮肤样本以及常见皮肤病、牛皮癣和湿疹患者的活检样本中的脂质进行分类,以期识别调节皮肤健康和疾病的新脂质。这些研究将确定脂质如何调节皮肤生物学,并可能设计出治疗炎症性皮肤病和伤口的新疗法。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A3, a Neutrophil-activating Eicosanoid.
  • DOI:
    10.1074/jbc.m115.700609
  • 发表时间:
    2016-06-24
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hinz C;Aldrovandi M;Uhlson C;Marnett LJ;Longhurst HJ;Warner TD;Alam S;Slatter DA;Lauder SN;Allen-Redpath K;Collins PW;Murphy RC;Thomas CP;O'Donnell VB
  • 通讯作者:
    O'Donnell VB
Lipidomic and transcriptional analysis of the linoleoyl-omega-hydroxyceramide biosynthetic pathway in human psoriatic lesions.
  • DOI:
    10.1016/j.jlr.2021.100094
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Tyrrell VJ;Ali F;Boeglin WE;Andrews R;Burston J;Birchall JC;Ingram JR;Murphy RC;Piguet V;Brash AR;O'Donnell VB;Thomas CP
  • 通讯作者:
    Thomas CP
Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.
  • DOI:
    10.4049/jimmunol.1402961
  • 发表时间:
    2015-07-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    McCully ML;Collins PJ;Hughes TR;Thomas CP;Billen J;O'Donnell VB;Moser B
  • 通讯作者:
    Moser B
The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles.
  • DOI:
    10.1371/journal.pone.0240189
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Rosas M;Slatter DA;Obaji SG;Webber JP;Alvarez-Jarreta J;Thomas CP;Aldrovandi M;Tyrrell VJ;Jenkins PV;O'Donnell VB;Collins PW
  • 通讯作者:
    Collins PW
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Valerie O'Donnell其他文献

Acutely-activated Monocytes and Macrophages Generate Several Families of Esterified LOX Products Including HETE, HpETE-and KETE-phospholipids
  • DOI:
    10.1016/j.freeradbiomed.2010.10.398
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Victoria Jayne Hammond;Alwena Morgan;Christopher Thomas;Valerie O'Donnell
  • 通讯作者:
    Valerie O'Donnell

Valerie O'Donnell的其他文献

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{{ truncateString('Valerie O'Donnell', 18)}}的其他基金

Systems Lipidomics tools and resources for biomedical research; LIPID MAPS.
用于生物医学研究的系统脂质组学工具和资源;
  • 批准号:
    MR/Y000064/1
  • 财政年份:
    2024
  • 资助金额:
    $ 104.77万
  • 项目类别:
    Research Grant
Funding for a QTrap Mass spectrometer for the Cardiff Lipidomic Group.
为 Cardiff Lipidomic Group 购买 QTrap 质谱仪提供资金。
  • 批准号:
    MR/X012247/1
  • 财政年份:
    2022
  • 资助金额:
    $ 104.77万
  • 项目类别:
    Research Grant
Mapping the lipid envelope composition of SARS-CoV2 for reducing transmission, thrombosis and inflammation
绘制 SARS-CoV2 的脂质包膜成分图,以减少传播、血栓形成和炎症
  • 批准号:
    BB/W003376/1
  • 财政年份:
    2021
  • 资助金额:
    $ 104.77万
  • 项目类别:
    Research Grant

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