The functional role and therapeutic potential of vascular niches in bone

几乎每两个人中就有一个患有骨病，给人民、卫生系统和政府造成了重大的健康负担。衰老与骨密度的丧失有关，这会增加骨折和骨折修复不良的风险，以及其他肌肉骨骼疾病。在骨髓移植和癌症治疗中，骨髓间室切除后骨丢失也很常见。了解骨周转的调节以及如何重建骨髓微环境可能会导致治疗骨丢失和相关骨病的新策略，这些疾病对普通人群的预期寿命延长构成了重大挑战。血管-统称为血管系统-为骨骼提供氧气和营养，并提供细胞表面或调节骨骼组织的分泌信号。骨血管与附近的间充质干细胞前体细胞相互作用，可以形成骨、脂肪细胞(脂肪细胞)和软骨。血管细胞和间充质干细胞相互作用，支持骨骼生长，为血液干细胞创造滋养环境。在衰老和骨丢失相关的疾病中，骨骼中脂肪细胞数量的增加干扰了有益的相互作用，并可能导致进一步的与年龄相关的血液和骨骼疾病。骨中有一种称为“H型”的血管，它是骨形成所必需的，也是发育中骨生长的关键调节因子。这些H型血管随着年龄的增长而减少，在骨质疏松时会进一步减少。某些激活血管系统的实验程序会导致间充质干细胞前体细胞数量的增加。这增加了以骨血管系统为靶点以刺激间充质细胞和刺激骨中的再生和治疗过程的令人兴奋的可能性。在这项拟议的研究中，我将询问血管在骨修复中的作用，特别关注血管系统与间充质干细胞产生骨和脂肪细胞的活性和潜力之间的相互作用。这些研究将首次深入了解控制间充质干细胞产生骨细胞和脂肪细胞的细胞类型和信号，以及这如何影响骨的发育和修复。这将通过揭示操纵血管系统以促进骨再生的策略而开辟新的天地，并可能确定管理骨病理的新策略。为了实现我的目标，我将结合尖端技术，如先进的高分辨率成像、我的东道主研究所(肯尼迪风湿病研究所)提供的复杂的可诱导细胞型特定小鼠模型，并以前所未有的方式利用我在骨血管形成和骨成像方面的成熟专业知识，以突破我们的理解极限。除了最先进的设施(如先进的成像、流式细胞仪)外，东道主研究所还提供不可或缺的本地合作(如JagDeep Nanchahal教授-骨折模型，Stephen Sansom博士-计算生物学)，接触人体样本(关节炎研究英国骨关节炎中心和纳菲尔德整形外科中心)，以使未来能够进行人体翻译，并提供辅导和职业发展培训，牛津大学的基础设施也提供理想的环境。综上所述，这个涉及再生医学、骨和血管生物学前沿的跨学科项目将对我独立职业生涯的建立做出重大贡献，使我能够保持在该领域的前沿，并发展自己的科学定位。

Bone disorders affect almost one in every two individuals posing a major health burden on people, health systems and the Government. Aging is associated with a loss of bone density, which increases risk of fractures and poor fracture repair, as well as other musculoskeletal disorders. Bone loss is also common after ablation of the bone marrow compartment in bone marrow transplantation and cancer therapy. Understanding regulation of bone turnover and how the bone marrow microenvironment can be re-established may lead to new strategies to treat bone-loss and associated bone disorders, which pose a major challenge with increasing life expectancy in the general populationBlood vessels - collectively referred to as the vasculature - supply bone with oxygen and nutrients and provide cell surface or secreted signals that regulate skeletal tissue. The bone vasculature interacts with nearby 'mesenchymal' stem progenitor cells that can give rise to bone, fat cells (adipocytes) and cartilage. Vascular cells and mesenchymal stem cells interact to support bone growth and create a nurturing environment for blood stem cells. In aging and bone loss-related disorders, an increase in the number of adipocytes in bone interferes with beneficial interactions and may lead to further age-related blood and bone diseases. A certain type of blood vessel in bone called "type H" is essential for bone formation and is a key regulator of developmental bone growth. These type H blood vessels decline during aging and are further reduced in osteoporosis. Certain experimental procedures that activate the vasculature lead to an increase in mesenchymal stem progenitor cell numbers. This raises the exciting possibility of targeting the bone vasculature to stimulate mesenchymal cells and to stimulate regenerative and therapeutic processes in the bone. In the proposed study, I will interrogate the contribution of blood vessels in bone repair, with a particular focus on the crosstalk between the vasculature and the activity and potential of mesenchymal stem cells to give rise to bone versus fat cells. These studies will provide the first insight into the cell types and signals that control production of bone cells and fat cells by mesenchymal stem cells, and how this impacts bone development and repair. This will break new ground by revealing strategies to manipulate the vasculature for bone regeneration, and may also identify novel strategies for managing bone pathologies. To achieve my goals, I will combine cutting-edge techniques like advanced high-resolution imaging, sophisticated inducible cell-type specific mouse models available within my host Institute (The Kennedy Institute of Rheumatology), and exploit my proven expertise in bone vascularization and bone imaging in an unprecedented manner to push the limits of our understanding. In addition to state-of-the-art facilities (e.g. advanced imaging, flow cytometry) host Institute provides indispensable local collaborations (e.g. Prof. Jagdeep Nanchahal - for fracture models, Dr. Stephen Sansom -computational biology), access to human samples (Arthritis Research UK Osteoarthritis Centre and Nuffield Orthopaedic Centre) to enable future translation to humans and the availability of mentoring and career development training, and access to Oxford University infrastructure offer an ideal environment. Taken together, this interdisciplinary project on the frontiers of regenerative medicine, bone and vascular biology will make a significant contribution towards the establishment of my independent career, allowing me to stay at the forefront of the field, and develop my own scientific niche.