Understanding and Preventing Inappropriate Osteogenic Differentiation

点击翻译按钮获取中文摘要

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.