Investigating the relationship between epilepsy, drug-resistance and affective disorders in the domestic dog

调查家犬癫痫、耐药性和情感障碍之间的关系

基本信息

批准号：
BB/P001874/1
负责人：
Holger Volk
金额：
$ 38.76万
依托单位：
Royal Veterinary College
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP001874%2F1
关键词：
Investigating relationship between epilepsy drug

项目摘要

Epilepsy is a complex brain disease, in which individuals are pre-disposed to show spontaneous seizures. Idiopathic epilepsy (IE) is classified as epilepsy of predominantly genetic or presumed genetic origin and in which there are no gross abnormalities of the structure of the brain nor other relevant underlying diseases causing seizure activity. IE is the most common chronic neurological condition in domestic dogs, estimated to affect 0.6% of dogs, but markedly higher in some breeds e.g. 17-33% in the Belgian Shepherd. Quality-of-life is also limited by side-effects of the currently used anti-epileptic drugs (AEDs), and quantity-of-life is potentially reduced due to an increased risk of premature death secondary to epilepsy. Further challenges faced by veterinarians treating dogs with epilepsy, and owners of affected dogs ARE (i) drug-resistance: a lack of response to currently available AEDs affecting up to 60-86% of treated dogs, and (ii) neurobehavioural changes comorbid with IE, which are poorly understood in dogs but highly prevalent in people with epilepsy. Our own studies have previously found that as few as 14% of dogs become seizure free on treatment, and increases in fear/anxiety and defensive aggression are seen following the onset of IE. These common features make the dog an ideal translational model for spontaneously occurring drug resistant epilepsy.It is clear that there is a need to gain a deeper understanding of IE in the dog to identify risk factors for (i) the development of IE, (ii) the lack of response to available AED therapies, (iii) the development of behavioural changes, and (iv) the interplay between these factors, so that future efforts to treat or prevent IE are targeted and effective. Genetic markers of both epilepsy and AED response have had limited success thus far, may be hard to interpret and account for only a limited proportion of susceptibility. In this study we instead investigate biochemical by-products of metabolic pathways (the 'metabolome') and the microorganisms living in association with the body (the 'microbiome') which reflects the interaction between an organism's genome and its environment and are a better potential indicator of observed characteristics, which can be potentially modified as treatment strategy. Although metabolomic markers of IE have not yet been found, profiles of anxiety have been identified in humans and mice. The microbiome has not yet been studied in IE development, but is involved in the metabolism of AEDs, and changes have been associated with anxiety levels through brain-gut interactions. This research programme will characterise types of disease presentation, the variation in behavioural characteristics, variation in metabolites in the metabolome, and differences in micro-organism populations in the microbiome in dogs with and without IE to identify novel biological markers of both the disease, drug response and behavioural signs (and associations between these factors) that could provide new perspectives on the underlying disease biology and provide new treatment targets. We will study these novel measures in two stages: firstly, a case-control study of breed and age-matched dogs with and without IE recruited from our hospital populations to directly compare profiles; secondly, a prospective cohort study of 5000 puppies from the South of England to identify physical and behavioural profiles measured before seizure onset that act as risk factors for IE development. Urine and faecal samples will be collected for metabolomic and microbiomic analysis. Behavioural testing will characterise aspects of the dogs' underlying affective state, to reveal whether IE and drug-resistance are associated with an underlying characteristic that predisposes individuals to perform anxiety-related behaviours. This novel and comprehensive approach is needed to unravel the mechanisms underlying IE, the occurrence of drug-resistance and behavioural abnormalities.

癫痫是一种复杂的脑部疾病，在该疾病中，个体被预先显示出自发性癫痫发作。特发性癫痫（IE）被归类为主要是遗传或假定遗传起源的癫痫，其中脑结构没有严重的异常，也没有其他相关的潜在疾病引起癫痫发作。 IE是家犬中最常见的慢性神经系统状况，估计会影响0.6％的狗，但在某些品种中显着高，例如比利时牧羊人17-33％。生活质量还受到当前使用的抗癫痫药（AED）的副作用的限制，并且由于癫痫病继发的早期死亡的风险增加，寿命可能会降低。兽医对癫痫的治疗狗面临的进一步挑战，受影响的狗的所有者是（i）抗药性：缺乏对当前可用的AED的反应，影响了多达60-86％的狗，以及（ii）神经be虫与IE的神经性变化，在狗中有很大的理解，这些变化在狗中却颇为普遍，但在Epilep中却充满了预期。我们自己的研究以前发现，只有14％的狗在治疗时无癫痫发作，并且在IE发作后看到了恐惧/焦虑和防御性侵略性的增加。这些常见特征使狗成为自发发生耐药性癫痫的理想翻译模型。很明显，有必要对狗的IE进行更深入的了解，以确定（i）IE的发展风险因素，（ii）（ii）缺乏对可用AED疗法的反应，（iii）行为变化和（iiv）对这些因素和（iiv）的发展和（iv）的发展，以及IE的目标，或者是IE的目标，或者是IE，或者是IE，也是如此。到目前为止，癫痫和AED反应的遗传标记均取得了有限的成功，可能很难解释和解释有限的易感性。在这项研究中，我们相反，我们研究了代谢途径（“代谢组”）的生化副产品和与身体（“微生物组”）相关的微生物，反映了生物体的基因组及其环境之间的相互作用，并且是预测特征的更好的潜在指标，这些特征可能是治疗策略的潜在特征。尽管尚未发现IE代谢标记，但在人类和小鼠中却发现了焦虑的特征。微生物组尚未在IE开发中进行研究，但参与了AED的代谢，并且通过大脑相互作用与焦虑水平有关。该研究计划将表征疾病表现的类型，行为特征的变化，代谢组中的代谢产物的变化以及有或没有IE的狗的微生物组中微生物种群的差异，以识别IE的新型生物学标记，以识别疾病，药物反应，行为迹象和行为迹象（以及这些因素之间的疾病）的新疾病，这些疾病可以提供新的疾病，这些疾病可以为新的疾病提供新的疾病。我们将在两个阶段研究这些新型措施：首先，对有或没有从医院人群招募的IE招募的品种和年龄匹配的狗进行病例对照研究，以直接比较概况；其次，一项对来自英格兰南部的5000只幼犬的前瞻性队列研究，以识别在发作发作之前测量的身体和行为特征，该素材是IE发育的危险因素。将收集尿液和粪便样品进行代谢组和微生物分析。行为测试将表征狗潜在的情感状态的各个方面，以揭示IE和抗药性是否与一种潜在的特征相关，使个人容易执行与焦虑相关的行为。需要这种新颖而全面的方法来揭示IE的机制，耐药性和行为异常的发生。