Aetiopathogenesis and genomic architecture of resistance to claw horn disruption lesions in dairy cattle

保持良好的足部健康是当今乳制品行业面临的最关键挑战之一。这是因为足部健康状况不佳导致动物的活动性降低并导致跛行。后者是一种使人衰弱和痛苦的疾病，被描述为奶牛福利受损的最明显指标之一，也是非自愿更换动物的最重要因素之一。没有其他常见的疾病与这种明显的疼痛症状有关，因此，奶牛跛行损害了公众对该行业的看法。最近的研究表明，英国近一半的奶牛在其生命的某个阶段面临活动能力降低和跛行问题，乳制品行业每年损失约2.5亿英镑。疼痛性足部病变占奶牛活动能力降低和跛行病例的90%以上。这些病变大致分为两类：感染性疾病，如趾皮炎和趾间皮炎，以及非感染性爪角破裂病变（CHDL），如足底出血、足底溃疡和白色线病。CHDL是英国和世界范围内与奶牛活动能力受损和疼痛相关的最常见疾病。在我们小组最近的一项研究中，44%的奶牛在12个月的监测期间发生了CHDL（足底出血、足底溃疡和白色线病分别为26%、12%和19%）。尽管CHDL很重要，但导致其发生的原因尚未完全描述。足部的解剖结构、动物激素和免疫概况、产犊周围的炎症、动物代谢和管理实践被认为是促成因素。个体动物对CHDL发展的易感性之间也存在遗传差异。在这个项目中，所有这些因素将一起研究使用大量的动物（3,000荷斯坦奶牛）饲养在四个英国商业农场。因此，该项目将（i）确定和量化影响CHDL发展的不同因素的影响，（ii）确定和量化动物对CHDL发展的抗性的遗传背景，以及（iii）制定实用的育种策略和工具，以减少CHDL的发生率，同时保持其他重要动物性状（生育力，对其他疾病的抗性和生产力）的改善。为了实现其目标，该项目将利用动物科学、兽医学、遗传学、生物技术、生物信息学、分子病理学、免疫学、显微镜和流行病学方面的互补专业知识，招募怀孕奶牛参加该项目。饲养这些动物的农场已经确定，并同意参加。从产犊前60天至随后的泌乳前半期，由合格兽医对动物进行密切监测。将系统记录CHDL、趾垫厚度（足部的保护性解剖结构）、血液中的激素水平、血液和组织中指示炎症的特定蛋白质、血液中指示代谢改变的酸水平以及奶牛活动和休息模式，生成相关信息的独特数据库。将生成个体牛基因组图谱并与奶牛测量结果一起进行分析，以评估环境和遗传对CHDL的影响。使用先进的测序技术将试图了解导致足部病变发展的潜在分子机制。最后，将设计模拟研究来评估不同的育种策略和工具，目的是将对CHDL的抗性培育到奶牛种群中。该项目的结果可能会通过支持有效管理实践、新育种工具和新药物干预的发展来显著改善动物健康和福利。

Maintaining good foot health is one of the most critical challenges the dairy industry faces today. This is because poor foot health leads to reduced mobility of the animal and causes lameness. The latter is a debilitating and painful condition, and is described as one of the clearest indicators of compromised welfare in dairy cattle and one of the most important factors for the involuntary replacement of animals. No other common condition is associated with such visible signs of pain and, as such, cow lameness damages the public's perception of the industry. Recent studies have suggested that nearly half the dairy cows in the UK face reduced mobility and lameness issues at some point in their life, costing the dairy sector approximately £250 million annually.Painful foot lesions account for more than 90% of reduced cow mobility and lameness cases. These lesions broadly fall under two categories: infectious diseases such as digital dermatitis and interdigital phlegmon, and non-infectious claw horn disruption lesions (CHDL) such as sole haemorrhages, sole ulcers and white line disease. CHDL are the most prevalent conditions associated with impaired mobility and pain in dairy cattle in the UK and worldwide. In a recent study by our group, 44% of cows developed CHDL during 12 months of monitoring (26%, 12% and 19% for sole haemorrhages, sole ulcers and white line disease, respectively).Despite the importance of CHDL, the reasons leading to their development have not yet been fully described. The anatomic structure of the foot, animal hormonal and immune profiles, inflammation around calving, animal metabolism, and management practices have been thought to contribute. There are also genetic differences between individual animal susceptibility to CHDL development. In this project, all these factors will be studied together using a large number of animals (3,000 Holstein cows) raised in four UK commercial farms. As a result, the project will (i) determine and quantify the impact of different factors affecting the development of CHDL, (ii) identify and quantify the genetic background of animal resistance to the development of CHDL and (iii) develop practical breeding strategies and tools to reduce the incidence of CHDL while maintaining improvement in other important animal traits (fertility, resistance to other diseases and productivity). To achieve its objectives, the project will draw on complementary expertise in animal science, veterinary medicine, genetics, biotechnology, bioinformatics, molecular pathology, immunology, microscopy and epidemiology.Animals recruited for this project will be pregnant cows. The farms where these animals are raised have already been identified and have agreed to participate. Animals will be closely monitored by a qualified veterinarian from 60 days before calving through to the first half of the ensuing lactation. Systematic recording of CHDL, the thickness of the digital cushion (a protective anatomical structure of the foot), hormonal levels in blood, specific proteins in blood and tissues indicative of inflammation, acid levels in blood indicative of altered metabolism, and cow activity and resting patterns will take place, generating a unique database of relevant information. Individual cattle genomic profiles will be generated and analysed together with cow measurements to assess the environmental and genetic impact on CHDL. Using advanced sequencing technologies will try to understand the underlying molecular mechanisms that lead to the development of foot lesions. Finally, simulation studies will be designed to evaluate different breeding strategies and tools with the aim to breed resistance to CHDL into the dairy cattle population.Outcomes of this project may improve considerably animal health and welfare by underpinning the development of efficient management practices, new breeding tools and novel pharmaceutical interventions.