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。这是因为脚部健康状况不佳导致动物的机动性降低并导致跛行。后者是一种使人衰弱和痛苦的状况，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。没有其他常见的情况与如此明显的疼痛迹象有关，因此，牛跛足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行动不便和跛行问题，每年使乳制品行业损失约2.5亿英镑。足部疼痛病变占90%以上的奶牛活动能力降低和跛行病例。这些病变大致分为两类：感染性疾病，如指间皮炎和指间痰，以及非感染性爪角破裂病变（CHDL），如足底出血、足底溃疡和白线病。在英国和世界范围内，CHDL是与奶牛活动能力受损和疼痛相关的最普遍的疾病。在我们小组最近的一项研究中，44%的奶牛在12个月的监测期间患上了冠心病（分别为26%、12%和19%的足底出血、足底溃疡和白线病）。尽管CHDL很重要，但导致其发展的原因尚未得到充分描述。足部的解剖结构、动物的激素和免疫特征、产犊周围的炎症、动物的新陈代谢和管理方法被认为是造成这种情况的原因。个体动物对CHDL的易感性也存在遗传差异。在这个项目中，所有这些因素将通过在四个英国商业农场饲养的大量动物（3000头荷斯坦奶牛）一起研究。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的发病率，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、显微镜学和流行病学方面的互补专业知识。该项目招募的动物将是怀孕的奶牛。饲养这些动物的农场已经确定，并同意参与。从产犊前60天到随后的哺乳期前半部分，将由合格的兽医密切监测动物。系统记录CHDL、数字垫（足部的一种保护性解剖结构）的厚度、血液中的激素水平、指示炎症的血液和组织中的特定蛋白质、指示代谢改变的血液中的酸水平、以及奶牛的活动和休息模式，将产生一个独特的相关信息数据库。将生成单个牛的基因组图谱，并与牛的测量数据一起进行分析，以评估环境和基因对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，目的是在奶牛种群中培育出对CHDL的抗性。该项目的成果可通过支持开发有效的管理做法、新的育种工具和新的药物干预措施，大大改善动物的健康和福利。

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.