Understanding and Preventing Inappropriate Osteogenic Differentiation

影响受过某种创伤的人的主要问题之一是异位骨化。这影响了22%的脊柱损伤病例、11%的创伤性脑损伤病例和65%的服务人员因爆炸而受伤。异位骨化是骨组织在非骨结构中的生长，如肌肉。骨骼在软组织位置的发育被认为是不适当的分化。它会导致活动减少，并使患者感到虚弱的疼痛。开发这种疾病的治疗方法的问题之一是，生物机制，甚至是转化为骨骼的细胞，仍然未知。在这项研究方案中，我们建议利用毛囊中发现的一种细胞类型，这种细胞在正确的刺激条件下可以转化为骨骼。就像个体在受伤后出现的异位骨化一样，这种从毛囊细胞发育而来的骨骼被认为是不适当的分化。我们将使用这些毛囊细胞来试图揭示损伤激活导致异位骨化的生物学机制。在我们的第一个目标中，我们将利用一种改进的激波管的可用性，它可以在实验室环境中复制爆炸损伤，以模拟从皮肤和毛囊分离的细胞中的损伤。我们将看看机械损伤本身是否能“刺激”毛囊细胞，并将它们转化为骨细胞。这将帮助我们了解机械损伤是否会刺激即将成为骨骼的细胞，或者它们是否会刺激身体内的其他细胞，然后这些细胞向周围的细胞发送信号，将它们转变为骨骼。我们的第二个目标是建立机械损伤前后毛囊细胞和骨骼发育的基因图谱，了解为什么毛囊细胞具有这种有趣的特性，使它们能够转化为骨。这可能有助于确定防止骨形成的治疗靶点。最后，第三个目标是筛选一些小分子和药物，看看它们中是否有任何一种可以防止毛囊细胞变成骨。第三个目标的概念是确定潜在的小分子，这些小分子可以在临床上用于预防或减少创伤后患者观察到的异位骨化。整个方案利用了从头皮活检中分离出来的人类细胞。因此，我们正在评估与人体细胞模型中不适当的骨形成有关的途径和基因，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，以防止或逆转异位骨化。

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.