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MICA:The Potential of Multipoint Adult Progenitor Cells as a Novel Therapeutic Strategy in Alcoholic Hepatitis

MICA：多点成体祖细胞作为酒精性肝炎新治疗策略的潜力

基本信息

批准号：
MR/S001581/1
负责人：
Reenam Khan
金额：
$ 43.72万
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS001581%2F1
关键词：
MICA Potential Multipoint Adult Progenitor

项目摘要

Liver disease accounts for one in ten of all deaths in people between the ages of 40 and 49 and costs the NHS £1 billion every year. Alcohol is a major cause of liver disease. One way in which alcoholic liver disease can present is alcoholic hepatitis, which is a very dramatic condition with a high mortality, despite current treatments. Therefore, we urgently need to find new treatments for this condition. Understanding the way in which alcohol results in alcoholic hepatitis can help us to identify potential targets for developing new treatments. Due to previous research, we know which types of cells are responsible for causing liver damage in alcoholic hepatitis. If we can find an effective way of reducing the numbers of these harmful cells getting into the liver, this can be possibly be used to treat alcoholic hepatitis. The most common cause of death in patients with alcoholic hepatitis is infection. Strengthening our body's response against infection is another way of reducing the number of deaths from alcoholic hepatitis.Several researchers have suggested that certain cells found in the bone marrow, called multipotent adult progenitor cells (MAPC), can help to reduce inflammation. In test-tube studies, animal studies and clinical trials, these cells have been shown to reduce the inflammation associated with a number of conditions, including heart attack and stroke. It has also been shown that bone marrow cells can improve the ability of cells to fight infection. After being injected in over 100 humans so far, it appears that MAPC injections are safe. However, it is unclear exactly how the MAPC work, or whether they could be used in treatment of alcoholic hepatitis. Testing the effectiveness and safety of treatments in mice before they are used in humans aims to minimise the risk of harm to patients. In our department, we have developed a method to induce alcoholic hepatitis in mice. Using human blood samples from alcoholic hepatitis patients, I can see if the findings in mice are comparable to those in humans, and therefore whether we can use the mouse experiments to accurately predict what will happen in humans.To assess the usefulness of MAPC in alcoholic hepatitis, I am then going to treat mice with these cells, and assess whether they reduce liver injury. Then I am going to do further experiments to investigate how these cells achieve their effect. For example, I am going to investigate whether MAPC prevent inflammatory cells from entering the liver, and determine exactly which molecules and cells are implicated in this. I will also be testing whether MAPC affect the ability to cells to clear infection. Using human cells in my laboratory work to supplement mouse experiments will help to ensure that my work will be applicable to humans. If we can define the exact mechanisms of action of MAPC, we can refine our treatments to maximise the intended benefits and minimise side effects. These studies will work together to help us to understand if MAPC can be used to treat alcoholic hepatitis and to find out the underlying mechanism.

在40岁至49岁的人群中，有十分之一的人死于肝病，每年花费NHS 10亿英镑。酒精是导致肝脏疾病的主要原因。酒精性肝病的一种表现形式是酒精性肝炎，这是一种非常严重的疾病，死亡率很高，尽管目前有治疗方法。因此，我们迫切需要找到新的治疗方法。了解酒精导致酒精性肝炎的方式可以帮助我们确定开发新疗法的潜在目标。根据之前的研究，我们知道哪些类型的细胞会导致酒精性肝炎的肝损伤。如果我们能找到一种有效的方法来减少这些进入肝脏的有害细胞的数量，就有可能用于治疗酒精性肝炎。酒精性肝炎患者最常见的死亡原因是感染。加强我们身体对感染的反应是减少酒精性肝炎死亡人数的另一种方法。几位研究人员提出，在骨髓中发现的某些细胞，称为多能成人祖细胞（MAPC），可以帮助减少炎症。在试管研究、动物研究和临床试验中，这些细胞已被证明可以减少与心脏病发作和中风等多种疾病相关的炎症。研究还表明，骨髓细胞可以提高细胞抵抗感染的能力。到目前为止，在100多人身上注射了MAPC后，似乎是安全的。然而，目前尚不清楚MAPC究竟是如何起作用的，也不清楚它们是否可以用于治疗酒精性肝炎。在用于人类之前，在小鼠身上测试治疗方法的有效性和安全性，目的是尽量减少对患者造成伤害的风险。在我科，我们开发了一种小鼠酒精性肝炎的诱导方法。使用酒精性肝炎患者的血液样本，我可以看到在小鼠身上的发现是否与在人类身上的发现相当，因此我们是否可以使用小鼠实验来准确预测在人类身上会发生什么。为了评估MAPC在酒精性肝炎中的作用，我将用这些细胞治疗小鼠，并评估它们是否减轻肝损伤。然后我将做进一步的实验来研究这些细胞是如何达到它们的效果的。例如，我将研究MAPC是否阻止炎症细胞进入肝脏，并确定哪些分子和细胞与此有关。我还将测试MAPC是否会影响细胞清除感染的能力。在我的实验室工作中使用人类细胞来补充小鼠实验将有助于确保我的工作适用于人类。如果我们能确定MAPC的确切作用机制，我们就能改进我们的治疗方法，使预期的益处最大化，副作用最小化。这些研究将共同帮助我们了解MAPC是否可以用于治疗酒精性肝炎，并找出其潜在的机制。