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Targeting activin receptors as a novel approach to promote myelin repair in the central nervous system

靶向激活素受体作为促进中枢神经系统髓磷脂修复的新方法

基本信息

批准号：
MR/M020827/1
负责人：
Veronique Miron
金额：
$ 152.38万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Fellowship
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

来源：
https://gtr.ukri.org/projects?ref=MR%2FM020827%2F1
关键词：
Targeting activin receptors novel approach

项目摘要

Oligodendrocytes are cells in the central nervous system that make myelin, an insulating layer around nerves that allows their normal functioning. Damage to myelin occurs in multiple sclerosis, contributing to lifelong problems with movement and sensation. Myelin repair can occur following this damage, and involves stem cells in the brain that multiply, survive and become new oligodendrocytes. However, as multiple sclerosis progresses, repair is less efficient and nerves don't function properly. Understanding what makes the stem cells multiply, survive, and become new oligodendrocytes is important in discovering new therapies that encourage myelin repair in MS. My studies show that a factor called activin-A is present in the brain during myelin repair, the stem cells in the injured brain have the receptors to respond to activin-A, and activation of these receptors can make these stem cells multiply, survive and become new oligodendrocytes in a dish. I predict that activin receptor activation in stem cells in the central nervous system drive myelin production and repair, and that activin receptors represent promising potential targets for a regenerative therapy for multiple sclerosis. The overall aim of my proposal is to understand how activin receptors control stem cell behaviour during myelin production and repair. The first objective is to identify when activin receptors could be activated on stem cells when myelin is being made or repaired, by looking at expression of activin receptors in the central nervous system of animal models.As there are multiple forms of activin receptors, the second aim is to determine which one of these can stimulate stem cells, by seeing if stem cells can still respond to activin-A when specific forms of activin receptors are no longer expressed. Loss of expression of specific activin receptors will be done using cutting edge modification of the stem cell DNA. These stem cells will then be analysed for ability to multiply, survive and become new oligodendrocytes, and signal activation patterns inside the cell.The third aim is to find out if other molecules that are known to activate activin receptors other than activin-A can also make stem cells multiply, survive, become oligodendrocytes and make myelin. Their expression in animal models when myelin is being made or repaired will be tested, and their effects on stem cell multiplication, survival and ability to become oligodendrocytes will be investigated.The fourth aim is to find out whether activin receptor activation on stem cells is needed for myelin to be made or repaired, using an animal model where the receptors aren't present on the stem cells and seeing whether myelin is still made or repaired. We will also test whether stimulating activin receptors, using activin-A or the other molecules identified above, is able to drive myelin repair in an animal model where it normally doesn't happen, to model the failed myelin repair in multiple sclerosis.The funding from this award would allow me to expand my research group, set up my independence and ask these important questions, which I believe could lead to the discovery of new strategies to encourage repair in multiple sclerosis. I believe that this research will show us the importance of activin receptors for stem cells in driving myelin repair, so that we can build on these findings to develop therapies for multiple sclerosis that stimulate these receptors.

少突胶质细胞是中枢神经系统中制造髓鞘的细胞，髓鞘是神经周围的绝缘层，允许它们正常运作。多发性硬化症患者会出现髓鞘损伤，导致终身的运动和感觉问题。髓磷脂修复可以在这种损伤后发生，并涉及大脑中的干细胞繁殖，存活并成为新的少突胶质细胞。然而，随着多发性硬化症的进展，修复效率降低，神经功能不正常。了解是什么使干细胞繁殖，存活并成为新的少突胶质细胞对于发现鼓励MS髓鞘修复的新疗法非常重要。我的研究表明，在髓鞘修复期间，大脑中存在一种称为激活素A的因子，受损大脑中的干细胞具有对激活素A做出反应的受体，这些受体的激活可以使这些干细胞繁殖，存活并在培养皿中成为新的少突胶质细胞。我预测，激活素受体激活干细胞在中枢神经系统驱动髓鞘的生产和修复，激活素受体代表有前途的潜在目标，为再生治疗多发性硬化症。我的提案的总体目标是了解激活素受体如何控制髓鞘产生和修复过程中的干细胞行为。第一个目标是通过观察动物模型中枢神经系统中激活素受体的表达，确定当髓鞘被制造或修复时，激活素受体何时可以在干细胞上被激活。由于有多种形式的激活素受体，第二个目标是确定其中哪一种可以刺激干细胞，通过观察当特定形式的激活素受体不再表达时，干细胞是否仍能对激活素A产生反应。将使用干细胞DNA的尖端修饰来完成特异性激活素受体表达的丧失。这些干细胞将被分析其增殖、存活和成为新的少突胶质细胞的能力，以及细胞内的信号激活模式。第三个目标是发现除了激活素A之外，其他已知激活激活素受体的分子是否也能使干细胞增殖、存活、成为少突胶质细胞和制造髓鞘。将测试它们在动物模型中在髓磷脂被制造或修复时的表达，并将研究它们对干细胞增殖、存活和成为少突胶质细胞的能力的影响。第四个目标是发现髓磷脂的制造或修复是否需要干细胞上的激活素受体激活，使用一种动物模型，在这种模型中，干细胞上没有这种受体，并观察髓鞘是否仍然被制造或修复。我们还将测试使用激活素A或其他上述分子刺激激活素受体是否能够在动物模型中驱动通常不会发生的髓鞘修复，以模拟多发性硬化症中失败的髓鞘修复。该奖项的资助将使我能够扩大我的研究小组，建立我的独立性并提出这些重要问题，我相信这将有助于发现新的策略来促进多发性硬化症的修复。我相信这项研究将向我们展示干细胞激活素受体在驱动髓鞘修复中的重要性，以便我们可以在这些发现的基础上开发刺激这些受体的多发性硬化症疗法。

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）

Early-life inflammatory markers and subsequent psychotic and depressive episodes between 10 to 28 years of age.

DOI：
10.1016/j.bbih.2022.100528
发表时间：
2022-12
期刊：
Brain, behavior, & immunity - health
影响因子：
0
作者：
通讯作者：

DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging.

DOI：
10.1212/wnl.0000000000012997
发表时间：
2021-12-07
期刊：
Neurology
影响因子：
9.9
作者：
Conole ELS;Stevenson AJ;Muñoz Maniega S;Harris SE;Green C;Valdés Hernández MDC;Harris MA;Bastin ME;Wardlaw JM;Deary IJ;Miron VE;Whalley HC;Marioni RE;Cox SR
通讯作者：
Cox SR

Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion