Fat-Hippo regulation of osteoblast differentiation

Fat-Hippo 对成骨细胞分化的调节

• 批准号: BB/K008668/1
• 负责人: Philippa Francis-West
• 金额: $ 50.52万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK008668%2F1
• 关键词: Fat; Hippo; regulation; osteoblast; differentiation

Bone is essential in both humans and animals. Bone enables us to move, protects our internal organs such as our heart and brain and is important for other aspects of our health such as kidney function. Bone is generated by bone-making cells called osteoblasts. Without osteoblasts, bone cannot be made. The aim of this proposal is to understand how two factors called Dchs1 and Fat4 control how osteoblasts develop. This will be a major advance because these factors are vital parts of a brand new type of cell control - this makes our application timely and exciting. We have shown that when Dchs1 and Fat4 are absent, the bones form but they do not grow properly ; they are smaller and softer. The little we know about these new Dchs1 and Fat4 factors indicates that their function is to instruct cell behaviour e.g. move in a certain direction, alter cell shape or they inhibit growth of cells and promote the formation of specialized cell types within the body. We will determine how Fat4 and Dchs1 control the osteoblast which make bone. Defects in bone development are relatively common and can result in severe deformities such as sciolosis, the curvature of the spine, and osteoporosis, the loss of bone which occurs frequently in post-menopausal women. Any bone loss will increase the chances of bone fracture. The elderly are particularly vulnerable to falls and fractures which typically lead to increased morbidity and mortality. Similar fractures due to weaker bones are also common in many animals particularly production poultry.The current proposal will discover new ways of controlling osteoblast behavior in order that we will be able to repair bone defects more quickly and increase bone mass by stimulating the bodies own cells to make bone or by generating more new osteoblasts using stem cell techniques. The aim is also to delay bone loss during ageing which diminish fracture incidence in both animals and humans. Both of these aims would have significant impact on a population's health and well being particularly of the aged.

骨骼对人类和动物都是必不可少的。骨骼使我们能够移动，保护我们的内部器官，如我们的心脏和大脑，并对我们健康的其他方面，如肾功能很重要。骨是由造骨细胞生成的。没有成骨细胞，就不能制造骨骼。该提案的目的是了解两种称为Dchs 1和Fat 4的因子如何控制成骨细胞的发育。这将是一个重大的进步，因为这些因素是一个全新的细胞控制类型的重要组成部分-这使得我们的应用及时和令人兴奋。我们已经证明，当Dchs 1和Fat 4缺失时，骨骼形成，但它们不能正常生长;它们更小更软。我们对这些新的Dchs 1和Fat 4因子知之甚少，这表明它们的功能是指导细胞行为，例如向某个方向移动，改变细胞形状或抑制细胞生长，促进体内特殊细胞类型的形成。我们将确定Fat 4和Dchs 1如何控制造骨细胞。骨发育缺陷相对常见，并可导致严重畸形，如脊柱侧弯、脊柱弯曲和骨质疏松症，绝经后妇女经常发生的骨丢失。任何骨质流失都会增加骨折的机会。老年人特别容易发生福尔斯和骨折，这通常导致发病率和死亡率增加。由于骨骼较弱而导致的类似骨折在许多动物中也很常见，特别是家禽。目前的提案将发现控制成骨细胞行为的新方法，以便我们能够通过刺激身体自身细胞制造骨骼或通过使用干细胞技术产生更多新的成骨细胞来更快地修复骨缺损并增加骨量。其目的还在于延缓衰老过程中的骨质流失，从而减少动物和人类的骨折发生率。这两个目标将对人口的健康和福祉，特别是老年人的健康和福祉产生重大影响。

项目成果

Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis.

• DOI: 10.1038/ncomms11469
• 发表时间: 2016-05-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mao Y;Kuta A;Crespo-Enriquez I;Whiting D;Martin T;Mulvaney J;Irvine KD;Francis-West P
• 通讯作者: Francis-West P

Making and shaping endochondral and intramembranous bones.

• DOI: 10.1002/dvdy.278
• 发表时间: 2021-03
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Galea GL;Zein MR;Allen S;Francis-West P
• 通讯作者: Francis-West P

Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.

• DOI: 10.1093/cercor/bhy058
• 发表时间: 2018-06-01
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Suetterlin P;Hurley S;Mohan C;Riegman KLH;Pagani M;Caruso A;Ellegood J;Galbusera A;Crespo-Enriquez I;Michetti C;Yee Y;Ellingford R;Brock O;Delogu A;Francis-West P;Lerch JP;Scattoni ML;Gozzi A;Fernandes C;Basson MA
• 通讯作者: Basson MA