Identification of Novel Drug Targets for Osteoporosis through Characterisation of the Genetic Basis of High Bone Mass

骨质疏松症是一种由骨骼变薄引起的常见疾病。它会随着年龄的增长而恶化，使骨头更容易断裂。在50岁以上的人群中，三分之一的女性和五分之一的男性会因为骨质疏松症而骨折。骨折会对活动能力、独立性和预期寿命造成严重影响。目前大多数骨质疏松症治疗的重点是防止进一步的骨质流失，而不是重建骨骼。研究发现，长期使用这些疗法实际上会增加某些罕见骨折的风险，而且很少会对颌骨造成损害。在英国，只有一种治疗方法（特立帕肽）可以帮助重建骨骼，但由于价格高昂，这种药物的使用受到限制，而且只能每天注射到皮肤中。需要更有效、负担得起和安全的口服治疗，以帮助重建骨骼和预防骨折。寻找新的骨质疏松症治疗方法之一是研究高骨量（HBM）人群。HBM很罕见，仅影响0.18%的人口。HBM患者的骨骼比正常人更厚，这意味着他们不太可能骨折。HBM是家族性的，但目前，我们还不知道导致HBM的所有基因。确定这些基因将有助于我们开发新的治疗方法，模仿这些基因的作用，帮助骨质疏松症患者重建骨骼。这种方法已经在美国成功地用于开发一种新的骨质疏松症治疗方法来重建骨骼（romosozumab）。然而，它与心脏病发作的风险增加有关，所以它并不适合所有人。英国布里斯托尔大学的HBM研究是迄今为止对极端HBM进行的最大研究。来自英国各地的355名HBM患者及其亲属收集了数据、血液样本和扫描结果。他们的遗传密码（DNA）已经被检查，并在18个家庭的DNA中发现了可能直接导致HBM的新变异（突变）。本研究旨在发现这些引起hbm的突变，并了解它们对骨形状、强度和生物学的影响。我的目标是：I)发现英国HBM个体的相同突变是否可以在其他HBM患者的DNA中找到。这将涉及分析来自几个人群的基因数据，其中包括在英国生物银行登记的多达50万人。ii)检查突变如何影响携带该突变的HBM个体和家族，特别是对其骨骼形状，结构和生物学的任何影响。iii)利用一系列基于计算机的工具和数据库确定包含突变的基因的功能及其在骨骼发育中的作用。我还将研究这些基因在斑马鱼骨骼中的作用。斑马鱼的骨骼结构和遗传密码与人类非常相似，因此可以帮助我们了解这些基因如何在人类中发挥作用。iv)使用基于计算机的工具和斑马鱼模型确定基因突变如何导致HBM。将测量对骨骼发育的影响，以预测对人类的可能影响。通过了解罕见基因突变如何导致HBM的生物学原理，我将能够找到治疗骨质疏松症的新方法。我将与布里斯托尔大学、伦敦国王学院和澳大利亚昆士兰大学的合作伙伴合作，帮助确保我的研究成果能够引领新的治疗方法的发展，这将直接使骨质疏松症患者受益。

Osteoporosis is a common condition caused by thinning of bones. It worsens with age and makes bones more likely to break (fracture). 1 in 3 women and 1 in 5 men over the age of 50 will break a bone in their lifetime because of osteoporosis. Fractures can have severe consequences on mobility, independence and life expectancy. Most current osteoporosis treatments focus on preventing further bone loss rather than rebuilding bone. Long term use of these treatments has been found to actually increase the risk of certain types of uncommon fractures and can rarely cause damage to the jaw. There is only one treatment available in the UK (teriparatide) which helps to rebuild bone but access to it is restricted due to high costs and it can only be given as daily injections into the skin. More effective, affordable and safe treatments are needed which can be taken by mouth to help rebuild bone and prevent fractures.One approach to finding new osteoporosis treatments is to study people who have High Bone Mass (HBM). HBM is rare, affecting only 0.18% of the population. HBM individuals have thicker/denser bones than normal which means they are less likely to break their bones. HBM runs in families but at present, we do not know all the genes that are responsible for causing HBM. Identifying these genes will help us to develop new treatments which mimic the actions of these genes and help rebuild bone for people suffering with osteoporosis. This approach has already been used successfully in the USA to develop a new osteoporosis treatment to rebuild bone (romosozumab). However, it has been linked to an increased risk of heart attacks, so it is not suitable for everyone. The UK HBM study at the University of Bristol is the largest study of extreme HBM performed to date. Data, blood samples and scans have been gathered from 355 HBM individuals and their relatives from across the UK. Their genetic code (DNA) has been examined and new variations (mutations) in the DNA of 18 families have been identified which may be directly responsible for causing HBM. This research aims to discover these HBM-causing mutations and understand their effects on bone shape, strength and biology. I aim to:i) Discover if the same mutations in UK HBM individuals can be found in the DNA of other people with HBM. This will involve analysing genetic data from several populations, including up to 500,000 people enrolled in the UK Biobank.ii) Examine how the mutation affects HBM individuals and families carrying that mutation, looking in particular for any effects on their bone shape, structure and biology.iii) Establish the function of the genes containing the mutations and their role in bone development using a range of computer-based tools and databases. I will also look at the role of these genes in the zebrafish skeleton. Zebrafish have a very similar bone structure and genetic code to humans, so can give us helpful insights into how these genes might work in humans.iv) Determine how gene mutations might cause HBM using computer-based tools and zebrafish models. The effect on bone development will be measured to predict the likely effects in humans.By understanding the biology of how rare gene mutations cause HBM, I will be able to find new ways to treat osteoporosis. I will work with partners at the University of Bristol, King's College London and the University of Queensland in Australia to help ensure the results of my research lead to the development of new treatments which will directly benefit patients with osteoporosis.