Deep phenotyping and precision medicine approaches to understand and treat autosomal dominant tubulointerstitial kidney disease due to UMOD mutations

研究罕见疾病使我们能够了解常见疾病的潜在过程，这些疾病往往有许多遗传和环境因素驱动疾病的发展。在这个项目中，研究罕见疾病，常染色体显性遗传性肾小管间质性肾病（ADTKD），将加强对慢性肾脏病（CKD）和肾纤维化（瘢痕形成）的潜在过程的理解，这影响了全球12%的人口，除了为受ADTKD影响的家庭找到特定的治疗方法。慢性肾脏病（CKD）是一种常见的、无声的和致命的疾病，治疗选择非常有限。ADTKD在家庭中以一种主导的方式运行，其中只需要一个基因的错误拷贝就可以让一半的孩子患上这种疾病。ADTKD导致CKD、终末期肾病和早发性痛风。ADTKD是遗传性CKD的三大原因之一，最常见的原因是UMOD基因中的错误拷贝（突变）。UMOD基因产生重要的蛋白质“尿调素”，这是人类尿液中最丰富的蛋白质，具有许多功能。 在继发于UMOD突变的ADTKD中，缺陷（突变）尿调蛋白在肾小管（肾脏过滤系统的一部分）细胞中积累，并引发肾间质纤维化（肾脏瘢痕形成）。ADTKD-UMOD患者表现为肾功能稳定下降，并且总是进展为需要透析或肾移植的终末期肾病。目前没有治疗方法。由于ADTKD直接导致肾脏瘢痕形成，因此它是一个很好的研究模型，有助于了解在一般人群中导致肾脏瘢痕形成和随后的CKD的原因，并找到治疗方法。 超过200个患有ADTKD的英国家庭同意将他们的医疗记录，尿液和血液样本用于研究。初步观察结果表明，这些家族中疾病进展的变异性很大，这表明修饰效应在起作用（与遗传疾病不直接相关，但影响ADTKD表达和严重程度的基因）。如果这些影响可以被识别，它将能够识别减轻疾病严重程度的细胞机制，这可能有助于针对这些患者的治疗。 一些基于人群的遗传学研究表明，UMOD基因的错误拷贝与一般人群中肾功能标志物和发生CKD和高血压的风险密切相关。尿调素具有多种功能;它可以防止尿路感染，防止肾结石的形成，减少急性肾损伤的伤害，调节肾脏中的盐运输，并激活先天免疫力。通过研究ADTKD，将更好地了解使Uromodulin发生故障的因素，这可能有助于预防和治疗一般人群中与UMOD或Uromodulin相关的各种肾脏问题。 在本项目中，将在一组超过200例ADTKD患者中明确并仔细定义疾病进展过程。然后，我们将详细研究导致更好和更坏结果的遗传和其他因素。然后，我们将使用来自患者尿液样本的肾细胞来模拟这种疾病，这样我们就可以更好地了解所涉及的细胞机制，并测试未来可能用于预防这种疾病中CKD进展的治疗方法。 该项目将使我们能够获得关于这种遗传形式的CKD的重要新知识，并为UMOD突变引起的CKD患者和大多数其他CKD原因（其中肾纤维化（瘢痕形成）是常见终点）的新疗法铺平道路。

Studying rare diseases enables us to understand the underlying processes of common diseases, which tend to have many genetic and environmental factors driving disease development. In this project, studying the rare disease, Autosomal dominant tubulointerstitial kidney disease (ADTKD), will enhance understanding of the underlying processes of Chronic Kidney Disease (CKD) and kidney fibrosis (scarring), which affects 12% of the global population, in addition to finding specific treatments for families affected by ADTKD. Chronic kidney disease (CKD) is a common, silent and deadly disease for which there are very limited treatment options. ADTKD runs in families in a dominant fashion, where only one faulty copy of a gene is required to give half of your children the disease. ADTKD causes CKD, end stage kidney disease and early onset gout. ADTKD is among the top three causes of genetic CKD and is most often caused by faulty copies (mutations) in the UMOD gene. The UMOD gene makes the important protein 'Uromodulin', which is the most abundant protein in the urine of humans and it has many functions. In ADTKD, secondary to UMOD mutations, faulty (mutant) uromodulin accumulates in the cells of the kidney tubules (part of the kidney's filtering system) and triggers renal interstitial fibrosis (scarring of the kidney). Patients with ADTKD-UMOD present with a steady decline in renal function and invariably progress to end stage kidney disease requiring dialysis or kidney transplantation. There are currently no treatments. As ADTKD directly causes kidney scarring, it is an excellent model to study to help understand what causes kidney scarring and subsequent CKD in the general population and find treatments. Over 200 UK families with ADTKD have consented for their medical records, urine and blood samples to be used for research. Initial observations indicate large degrees of variability in disease progression in these families, that suggests modifier effects are at work (genes that are not directly linked to the genetic disease but influence the expression and severity of ADTKD). If these effects can be identified, it will enable identification of the cellular mechanisms that moderate the disease severity which could help target treatments for these patients. A number of population-based genetic studies have shown that faulty copies of the UMOD gene are strongly linked with markers of kidney function and risk of developing CKD and high blood pressure in the general population. Uromodulin has many functions; it protects against urinary tract infections, it prevents the formation of kidney stones, it reduces harm from acute kidney injury, regulates salt transport in the kidney and activates innate immunity. By studying ADTKD, a greater understanding of the factors that make Uromodulin become faulty will be achieved, that could help prevent and treat a variety of kidney problems related to UMOD or Uromodulin in the general population. In this project, the course of disease progression will be clearly and carefully defined in a group of over 200 patients with ADTKD. We will then examine in detail the genetic and other factors that lead to better and worse outcomes. We will then use kidney cells derived from patient urine samples to model the disease so we can better understand cellular mechanisms involved and to test treatments that may be used in the future to prevent the progression of CKD in this disease. This project will allow us to gain significant new knowledge regarding this genetic form of CKD and pave the way towards new therapies for patients with CKD caused by UMOD mutations and most other causes of CKD where kidney fibrosis (scarring) is the common endpoint.