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

通过表征高骨量的遗传基础鉴定骨质疏松症的新药物靶点

• 批准号: MR/V00199X/1
• 负责人: Neelam Hassan
• 金额: $ 38.26万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV00199X%2F1
• 关键词: Identification; Novel; Drug; Targets; Osteoporosis

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.

骨质疏松症是由骨骼变薄引起的常见疾病。它随着年龄的增长而恶化，并使骨头更容易断裂（骨折）。 50 岁以上的女性中，有三分之一的女性和男性中有五分之一的人一生中会因骨质疏松症而骨折。骨折会对活动能力、独立性和预期寿命产生严重影响。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。人们发现，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，并且很少会对颌骨造成损害。英国只有一种治疗方法（特立帕肽）可以帮助重建骨骼，但由于成本高昂，使用受到限制，而且只能每天注射到皮肤中。我们需要更有效、负担得起且安全的口服治疗方法，以帮助重建骨骼并预防骨折。寻找新的骨质疏松症治疗方法的一种方法是研究高骨量 (HBM) 患者。 HBM 很罕见，仅影响 0.18% 的人口。 HBM 个体的骨骼比正常人更厚/更致密，这意味着他们骨折的可能性较小。 HBM 在家族中存在，但目前我们还不知道导致 HBM 的所有基因。识别这些基因将有助于我们开发模仿这些基因作用的新疗法，并帮助骨质疏松症患者重建骨骼。这种方法已在美国成功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，因此并不适合所有人。布里斯托大学的英国 HBM 研究是迄今为止最大规模的极端 HBM 研究。我们从英国各地 355 名 HBM 个体及其亲属收集了数据、血液样本和扫描结果。对它们的遗传密码 (DNA) 进行了检查，并确定了 18 个家族 DNA 中的新变异（突变），这些变异可能直接导致 HBM。这项研究旨在发现这些引起 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) 发现英国 HBM 个体中的相同突变是否可以在其他 HBM 患者的 DNA 中找到。这将涉及分析来自多个人群的遗传数据，包括英国生物库中登记的多达 500,000 人。ii) 检查突变如何影响携带该突变的 HBM 个体和家庭，特别是寻找对其骨骼形状、结构和生物学的影响。iii) 使用一系列基于计算机的工具和数据库建立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，因此可以为我们提供有关这些基因如何在人类中发挥作用的有用见解。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，以预测对人类可能产生的影响。通过了解罕见基因突变如何导致 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开发出新的治疗方法，从而直接造福骨质疏松症患者。

项目成果

High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench.

• DOI: 10.1002/jbmr.4715
• 发表时间: 2023-02
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Bergen, Dylan J. M.;Maurizi, Antonio;Formosa, Melissa M.;McDonald, Georgina L. K.;El-Gazzar, Ahmed;Hassan, Neelam;Brandi, Maria-Luisa;Riancho, Jose A.;Rivadeneira, Fernando;Ntzani, Evangelia;Duncan, Emma L.;Gregson, Celia L.;Kiel, Douglas P.;Zillikens, M. Carola;Sangiorgi, Luca;Hogler, Wolfgang;Duran, Ivan;Makitie, Outi;Van Hul, Wim;Hendrickx, Gretl
• 通讯作者: Hendrickx, Gretl

Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.

• DOI: 10.1002/jbmr.4795
• 发表时间: 2023-05
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Hassan, Neelam;Gregson, Celia L. L.;Tang, Haotian;van der Kamp, Marc;Leo, Paul;McInerney-Leo, Aideen M.;Zheng, Jie;Brandi, Maria Luisa;Tang, Jonathan C. Y.;Fraser, William;Stone, Michael D.;Grundberg, Elin;Brown, Matthew A.;Duncan, Emma L.;Tobias, Jonathan H.
• 通讯作者: Tobias, Jonathan H.

Anabolic treatments for osteoporosis in postmenopausal women.

• DOI: 10.12703/r/10-44
• 发表时间: 2021
• 期刊: Faculty reviews
• 作者: Hassan N;Gregson CL;Tobias JH
• 通讯作者: Tobias JH