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

骨质疏松症是一种常见的骨质疏松症。它会随着年龄的增长而恶化，使骨骼更容易骨折。1/3的女性和1/5的男性在50岁以上会因为骨质疏松而在一生中折断一根骨头。骨折可能会对行动能力、独立性和预期寿命造成严重后果。目前大多数骨质疏松症的治疗重点是防止进一步的骨丢失，而不是重建骨。长期使用这些治疗方法实际上会增加某些类型的罕见骨折的风险，而且很少会对颌骨造成损害。在英国，只有一种治疗方法(Teriparatide)可以帮助重建骨骼，但由于成本较高，获得这种药物的机会受到限制，只能每天向皮肤注射。需要更有效、更实惠和更安全的治疗方法，可以通过口服来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)患者。HBM很少见，仅影响0.18%的人口。HBM患者的骨骼比正常情况下更厚/更致密，这意味着他们不太可能骨折。HBM在家族中存在，但目前，我们还不知道所有导致HBM的基因。识别这些基因将帮助我们开发新的治疗方法，模仿这些基因的行为，并帮助患有骨质疏松症的人重建骨骼。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(Romosozumab)。然而，它被认为与心脏病发作的风险增加有关，所以它并不适合每个人。英国布里斯托尔大学的HBM研究是迄今为止对极端HBM进行的最大规模的研究。来自英国各地的355名HBM患者及其亲属收集了数据、血液样本和扫描数据。他们的遗传密码(DNA)已经被检查，并在18个家庭的DNA中发现了新的变异(突变)，这可能是引起HBM的直接原因。这项研究旨在发现这些导致HBM的突变，并了解它们对骨骼形状、强度和生物学的影响。我的目标是：i)发现在UK HBM个体中是否可以在其他HBM患者的DNA中发现相同的突变。这将涉及分析几个人群的基因数据，包括英国生物库登记的多达500,000人。ii)研究突变如何影响携带该突变的HBM个人和家庭，尤其是对他们的骨骼形状、结构和生物学有任何影响。iii)利用一系列基于计算机的工具和数据库来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。斑马鱼具有与人类非常相似的骨骼结构和遗传密码，因此可以帮助我们深入了解这些基因在人类中是如何发挥作用的。iv)利用计算机工具和斑马鱼模型来确定基因突变可能如何导致HBM。通过测量对骨骼发育的影响来预测对人类的可能影响。通过了解罕见的基因突变如何导致HBM的生物学，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，帮助确保我的研究结果有助于开发新的治疗方法，使骨质疏松症患者直接受益。

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.