Understanding and Preventing Inappropriate Osteogenic Differentiation

了解和预防不适当的成骨分化

• 批准号: MR/M01858X/1
• 负责人: Claire Higgins
• 金额: $ 51.34万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM01858X%2F1
• 关键词: Understanding; Preventing; Inappropriate; Osteogenic; Differentiation

One of the major issues affecting individuals who have recieved some sort of traumatic injury, is heterotopic ossification. This impacts 22% of spinal injury cases, 11% of traumatic brain injury cases, and 65% of service personnel injured by explosive blasts. Heterotopic ossification is the growth of bone tissue, in a non-bone structure, such as the muscle. The development of bone in a soft tissue location is regarded as inappropriate differentiation. It can result in decreased movement, and debilitating pain for the patient. One of the problems in developing treatments for this condition is that the biological mechanisms, and even the cells that are turning into bone, remain unknown. In this research proposal, we propose to utilise a cell type found in the hair follicle, which under the correct stimulating conditions can turn into bone. Like heterotopic ossification seen in individuals after injury, this development of bone from hair follicle cells is regarded as inappropriate differentiation. We will use these hair follicle cells to try and uncover the biological mechanisms that are activated by injury resulting in heterotopic ossification. In our first objective, we will exploit the availability of a modified shock tube that can replicate blast injury in a lab setting, to simulate injury in cells isolated from the skin and hair follicle. We will see if mechanical injury itself can 'stimulate' hair follicle cells, and turn them into bone cells. This will help us to understand if mechanical injury stimulates the cells that are to become bone, or whether they stimulate other cells in the body that then send signals to cells around them, turning them into bone. Our second objective is to establish a genetic profile of hair follicle cells before and after mechanical injury, and bone development, to understand why hair follicle cells have this interesting property, enabling them to turn into bone. This may help to identify therapeutic targets for preventing bone formation. Lastly, the third objective is to screen a number of small molecules, and drugs, to see if any of them can prevent hair follicle cells turning into bone. The concept of this third objective is to identify potential small molecules that could be used clinically to prevent or reduce the heterotopic ossification observed in patients after traumatic injury.This entire proposal utilises human cells, isolated from scalp biopsies. We are therefore assessing pathways and genes involved in inappropriate bone formation in a human cell model, making it ultimately translational for clinical application. Our overall goal is to identify new targets for therapeutic intervention, to prevent or reverse heterotopic ossification.

其中一个主要问题影响个人谁已经收到某种创伤性损伤，是异位骨化。这影响了22%的脊髓损伤病例，11%的创伤性脑损伤病例和65%的爆炸性爆炸受伤的服务人员。异位骨化是骨组织在非骨结构（如肌肉）中的生长。软组织部位的骨发育被认为是不适当的分化。它可能导致患者运动减少和衰弱性疼痛。开发这种疾病的治疗方法的问题之一是生物学机制，甚至是变成骨骼的细胞仍然未知。 在这项研究中，我们建议利用毛囊中发现的一种细胞类型，在正确的刺激条件下，这种细胞可以变成骨骼。就像在受伤后的个体中看到的异位骨化一样，毛囊细胞的骨发育被认为是不适当的分化。我们将利用这些毛囊细胞来尝试和揭示的生物学机制，是激活损伤导致异位骨化。在我们的第一个目标中，我们将利用一种可以在实验室环境中复制爆炸伤的改良激波管来模拟从皮肤和毛囊中分离的细胞的损伤。我们将看到机械损伤本身是否可以“刺激”毛囊细胞，并将其转化为骨细胞。这将有助于我们了解机械损伤是否刺激了将要成为骨骼的细胞，或者它们是否刺激了体内的其他细胞，然后向周围的细胞发送信号，将它们变成骨骼。我们的第二个目标是建立毛囊细胞在机械损伤和骨发育前后的遗传图谱，以了解为什么毛囊细胞具有这种有趣的特性，使它们能够变成骨。这可能有助于确定预防骨形成的治疗靶点。最后，第三个目标是筛选一些小分子和药物，看看它们是否可以阻止毛囊细胞变成骨骼。这第三个目标的概念是确定潜在的小分子，可用于临床，以防止或减少异位骨化后观察到的患者创伤injuries.This整个建议利用人类细胞，分离头皮活检。因此，我们正在评估人类细胞模型中不适当骨形成所涉及的途径和基因，使其最终转化为临床应用。我们的总体目标是确定治疗干预的新靶点，以预防或逆转异位骨化。

项目成果

Methods for the isolation and 3D culture of dermal papilla cells from human hair follicles.

• DOI: 10.1111/exd.13368
• 发表时间: 2017-06
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Topouzi H;Logan NJ;Williams G;Higgins CA
• 通讯作者: Higgins CA

Subpopulations of dermal skin fibroblasts secrete distinct extracellular matrix: implications for using skin substitutes in the clinic.

• DOI: 10.1111/bjd.16255
• 发表时间: 2018-08
• 期刊: The British journal of dermatology
• 作者: Ghetti M;Topouzi H;Theocharidis G;Papa V;Williams G;Bondioli E;Cenacchi G;Connelly JT;Higgins CA
• 通讯作者: Higgins CA

The Hair Follicle: An Underutilized Source of Cells and Materials for Regenerative Medicine.

• DOI: 10.1021/acsbiomaterials.7b00072
• 发表时间: 2018-04-09
• 期刊: ACS biomaterials science & engineering
• 影响因子: 5.8
• 作者: Kiani MT;Higgins CA;Almquist BD
• 通讯作者: Almquist BD