Rare early onset lower urinary tract disorders

罕见的早发性下尿路疾病

• 批准号: MR/Y008340/1
• 负责人: William Newman
• 金额: $ 146.89万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY008340%2F1
• 关键词: Rare; early; onset; lower; urinary

The problem.Many children in the UK suffer with significant bladder problems that result in bed-wetting, incontinence, urine infections and even severe kidney damage. In fact, rare bladder conditions are the commonest cause of kidney failure in children who can only be kept alive by dialysis and transplantation. Up to one in three children with severe bladder emptying problems also have constipation. Bowel and bladder problems have more impact than almost any other medical condition on children's self-esteem, education and social relationships.Our approach to the problem.Genes are the inherited instructions in our cells providing the information for how our bodies develop. We know that many genes are important in how the bladder and ureters (tubes connected to the kidneys) develop and work. We have discovered changes in a number of these genes in children with rare severe bladder problems. However, we have collected samples and clinical information from many children where we still do not have a genetic answer. This represents a significant unmet need. Through this rare disease node we will create a network of clinicians and researchers across the UK to collect samples and information from children affected by these conditions creating a registry of affected individuals and genetic samples for further study. We will work as a collaborative team to address these challenging problems and train and support the next generation of researchers and clinicians to care for affected families.We propose three answers: 1. to use new types of genetic analysis, where we can study structural changes in the genetic material in a cell, to find the causes of severe inherited bladder problems; 2. to look at how genes are switched on and off in the bladder and ureters in children with a severe condition called bladder exstrophy from samples taken at surgery and compare these patterns to healthy children. This will give us an insight into how the organs develop and how and why this may go wrong; and 3. we will look at new exciting ways to deliver genes to the body so that they may correct these conditions using an approach called gene therapy.Finding the responsible genes will allow us to: 1. give families the reason for their children's problems; 2. do simple genetic tests on other family members to see if they may require check-ups to detect and prevent the progression to severe bladder and kidney disease; and 3. start to understand the reasons that children are affected by these problems which will help to develop novel treatments. Furthermore, understanding rare inherited types of bladder problems can provide reasons as to why children have more common problems like bed-wetting and urine infections, which affect nearly one million UK children.We will organise meetings with affected families to discuss our work and seek input to guide the way that we approach these studies and share information about them through charities like ERIC, the Children's Bowel and Bladder Charity. The 2018 NHS England guidance on Excellence in Continence Care highlights the inequalities and need for improvements in clinical care for individuals with urinary and bowel incontinence.Because severe inherited bladder disorders can affect multiple family members their impact is greater. As most are inherited in an 'autosomal recessive' pattern (a genetic change inherited from each unaffected parent), these conditions are more common in communities where marriage within families occurs. In the UK there is a significant burden in families of Pakistani origin. In the Health Profile for England Report 2017, there was a threefold increased infant mortality in British Pakistanis and other measures of poorer health in this community. Therefore, supporting research in these disorders will have a major health benefit in a disadvantaged community.

问题：在英国，许多儿童患有严重的膀胱问题，导致尿床、尿失禁、尿液感染，甚至严重的肾损伤。事实上，罕见的膀胱疾病是儿童肾衰竭的最常见原因，他们只能通过透析和移植来维持生命。多达三分之一的患有严重膀胱排空问题的儿童也有便秘。肠道和膀胱问题对儿童的自尊、教育和社会关系的影响几乎比任何其他医疗条件都要大。我们解决问题的方法基因是我们细胞中的遗传指令，为我们的身体如何发育提供信息。我们知道许多基因对膀胱和输尿管（连接肾脏的管道）的发育和工作都很重要。我们发现患有罕见严重膀胱问题的儿童中许多基因发生了变化。然而，我们已经从许多儿童那里收集了样本和临床信息，我们仍然没有遗传答案。这是一个未得到满足的重大需求。通过这个罕见疾病节点，我们将在英国各地建立一个临床医生和研究人员网络，收集受这些疾病影响的儿童的样本和信息，为进一步研究建立受影响个体和遗传样本的登记册。我们将作为一个合作团队来解决这些具有挑战性的问题，并培训和支持下一代研究人员和临床医生照顾受影响的家庭。使用新型遗传分析，我们可以研究细胞遗传物质的结构变化，以找到严重遗传性膀胱问题的原因; 2.从手术中采集的样本中观察患有严重膀胱外翻的儿童的膀胱和输尿管中基因是如何开启和关闭的，并将这些模式与健康儿童进行比较。这将使我们深入了解器官如何发育，以及如何以及为什么会出错; 3.我们将寻找新的令人兴奋的方法来将基因传递到身体，这样他们就可以使用一种叫做基因治疗的方法来纠正这些状况。2找到负责的基因将使我们能够：1。让家庭了解孩子问题的原因; 2.对其他家庭成员进行简单的基因测试，看看他们是否需要检查，以发现和防止发展为严重的膀胱和肾脏疾病;以及3.开始了解儿童受这些问题影响的原因，这将有助于开发新的治疗方法。此外，了解罕见的遗传性膀胱问题可以解释为什么儿童会出现尿床和尿液感染等更常见的问题，这些问题影响着近一百万英国儿童。我们将组织与受影响家庭的会议，讨论我们的工作并寻求意见，以指导我们处理这些研究的方式，并通过ERIC、儿童肠道和膀胱慈善机构等慈善机构分享有关它们的信息。2018年英国国民保健署（NHS）关于失禁护理的卓越指南强调了对尿失禁和肠失禁患者临床护理的不平等和改善需求。由于严重的遗传性膀胱疾病可能影响多个家庭成员，因此其影响更大。由于大多数是以“常染色体隐性”模式遗传的（从每个未受影响的父母遗传的遗传变化），这些情况在家庭内部婚姻发生的社区中更常见。在英国，巴基斯坦裔家庭的负担很重。在2017年英格兰健康状况报告中，英国巴基斯坦人的婴儿死亡率增加了三倍，该社区的其他健康状况较差。因此，支持这些疾病的研究将在弱势群体中产生重大的健康益处。

项目成果

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

人类 HPSE2 基因转移改善尿面综合征突变小鼠模型的膀胱病理生理学

• DOI: 10.7554/elife.91828.1
• 发表时间: 2024
• 作者: Lopes F