Genetic and molecular mechanisms of kidney stone disease

肾结石很常见，近五分之一的男性在一生中都会患上肾结石。大约一半的肾结石患者会在10年内形成另一种肾结石。不幸的是，一些人导致肾结石的原因人们知之甚少，可用来防止更多结石形成的治疗方法也不是很有效。有人说，肥胖会增加患肾结石的风险，但具体是如何或为什么会增加，目前还不清楚。如果我们能更好地了解一些人形成肾结石的原因，以及肾结石和肥胖之间的联系，我们就可以设计出更好的治疗方法来预防这个问题。英国生物库是一项针对近50万人的研究，他们与研究人员分享了基因数据、身体测量、医疗记录和血液测试。我用这些数据表明，腰部脂肪较多的人更容易患肾结石，即使他们的身体质量指数正常。这表明，中心脂肪分布，而不是整体肥胖，是患肾结石的一个风险因素。我们从以前的研究中了解到，高血钙水平是肾结石的一个危险因素。查看英国生物银行的数据，我发现腰部脂肪较多的人也更有可能血液钙水平升高。这一结果部分地(但不完全)解释了为什么中枢脂肪分布增加会增加一个人患肾结石的风险。这项研究旨在提高我们对人们为什么会形成肾结石的理解。我将调查为什么高水平的中枢脂肪与肾结石和血钙水平升高有关。利用这些发现，我将为肾结石患者寻找新的治疗方法。该项目有三个主要阶段，将在世界领先的医学和基因研究中心牛津大学进行。在这个项目的第一阶段，我将使用英国生物库最新发布的基因数据。我将通过改变蛋白质的合成方式来确定增加个人患肾结石风险的DNA区域。这项工作将确定导致肾结石的途径，这是以前不知道的。为了确认我的发现是正确的，我将在其他大型数据集中进行类似的研究。在项目的第二阶段，我将使用英国生物库关于血液生物标记物的数据。生物标记物是体内的化学物质，在某些情况下可能会增加或降低水平。我会在中心脂肪分布较高的人群中寻找高或低的血液生物标志物。然后我会看看肾结石或高血钙患者的这些指标是否也发生了变化。一旦我确定了看起来很有趣的生物标记物，我将使用一种名为孟德尔随机化的遗传技术来找出这些生物标记物水平的变化是否与我正在研究的条件存在因果关系。在第一和第二阶段，我将确定与肾结石风险增加有关的途径和生物标记物。在第三阶段，我将使用基因技术来观察针对这些疾病的药物是否对治疗有帮助。我将寻找是否有任何现有的药物影响这些途径和生物标记物，并用于治疗其他疾病。我将评估这些药物是否可以用于肾结石患者。我的研究将提供信息，说明我们应该专注于开发哪些新药或现有药物，以帮助未来治疗肾结石患者。

Kidney stones are common and affect nearly 1 in 5 men in their lifetime. Around half of patients who develop a kidney stone will form another within 10 years. Unfortunately, the reasons why some people make kidney stones are poorly understood and the treatments available to prevent more stones forming are not very effective. It has been said that obesity increases the risk of kidney stones, but it is unclear exactly how or why. If we could better understand why some people form kidney stones, and the links between kidney stones and obesity, we could design improved treatments to prevent this problem. The UK Biobank is a study of nearly half a million people who have shared genetic data, physical measurements, medical records, and blood tests with researchers. I have used this data to show that people who carry more fat around their waist are more likely to get kidney stones, even if their body mass index is normal. This suggests that central fat distribution, not overall obesity, is a risk factor for developing kidney stones. We know from previous research that high blood calcium levels are a risk factor for kidney stones. Looking at the UK Biobank data, I found that people with more fat around their waist are also more likely to have an increased blood calcium level. This result partly, but not fully, explains why increased central fat distribution increases a person's risk of kidney stones. This study aims to improve our understanding of why people form kidney stones. I will investigate the reasons why high levels of central fat are linked to kidney stones and raised blood calcium levels. Using these findings, I will look for new treatments for patients with kidney stones. This project has three main stages and will be carried out at the University of Oxford, a world-leading centre for medical and genetic research. In the first stage of this project, I will use newly released genetic data from the UK Biobank. I will identify areas of DNA that increase an individual's risk of kidney stones by changing how proteins are made. This work will identify pathways that cause kidney stones that were not previously known. To confirm my findings are correct, I will undertake similar studies in other large datasets. In the second stage of the project, I will use the UK Biobank's data on blood biomarkers. Biomarkers are chemicals in the body that may have increased or decreased levels in certain conditions. I will look for blood biomarkers that are high or low in people with a high central fat distribution. I will then see if these are also altered in people with kidney stones or high blood calcium levels. Once I have identified biomarkers that look interesting, I will use a genetic technique called Mendelian randomisation to find out whether changes in the levels of these biomarkers are causally linked to the conditions I am studying. In stages one and two, I will identify pathways and biomarkers that are linked to an increased risk of kidney stones. In stage three, I will use genetic techniques to see if targeting these with medications may be helpful for treatment. I will look to see whether there are any existing medicines that affect these pathways and biomarkers and are used to treat other diseases. I will assess if these medicines could be used in patients with kidney stones. My studies will provide information about which new or current medications we should focus on developing to help treat people with kidney stones in the future.