Novel Pathway and Prevention Strategy for Heterotopic Ossification

描述（由申请人提供）：候选人：我将开始作为一个助理教授在密歇根大学的重点是烧伤和重建手术。我最近完成了为期两年的基础科学博士后奖学金，研究干细胞和骨生物学的基础和转化方法。我的长期职业目标是实现科学独立，并建立一个转化研究实验室，以改善烧伤，创伤性损伤和异位骨化（HO）患者的诊断和治疗策略。环境：我在最先进的医学科学和基础科学研究大楼内工作。我的主要导师，王博士是烧伤和创伤损伤，炎症通路和新型成像模式的研究人员。与王博士一起，我的顾问委员会包括骨生物学、炎症通路、干细胞、突变动物发育和体内成像方面的知名专家。研究：异位骨化是烧伤和创伤后常见的疾病。我们实验室的体外和体内模型的最新证据表明，烧伤增强了间充质干细胞（MSCs）的成骨能力，并刺激HO形成。新的机制见解表明，烧伤可能通过三磷酸腺苷（ATP）和smad依赖性骨形态发生蛋白受体1A（Bmpr 1a）信号传导发挥这种作用。当用ATP水解剂（腺苷三磷酸双磷酸酶）处理烧伤时，MSC和HO形成的这种成骨能力减弱。这些发现表明烧伤是HO形成的致病因素，腺苷三磷酸双磷酸酶是HO的预防策略。--目标1。确定烧伤对MSC成骨和异位骨化的促成骨作用的机制。在目标1A中，我们将研究烧伤对小鼠脂肪和骨髓间充质干细胞成骨能力的影响。除了使用来自Bmpr 1a突变小鼠的MSC之外，还将使用小分子BMP抑制剂。在目标1B中，我们将使用我们的跟腱切开术模型来探索烧伤对体内HO形成的作用。我们还将在整体Bmp抑制后将此模型应用于我们的Bmpr 1a突变小鼠，以进一步了解Bmpr 1a对HO的作用。--目的2：证明ATP水解对MSC和体内HO形成的抗成骨作用。在目标2A中，我们将优化ATP水解酶腺苷三磷酸双磷酸酶在我们的小鼠烧伤模型中的递送，并分析MSC的成骨能力。在目标2B中，我们将使用我们的跟腱切开术模型确定在烧伤部位应用腺苷三磷酸双磷酸酶是否可以阻断HO形成。这些结果将是至关重要的临床翻译的局部ATP水解作为一种预防策略，从HO。--总结：这个K 08提案的目的是为了方便我的目标，成为一个独立的外科医生科学家，重点是烧伤和异位骨化的进展。这个建议是我以前在MSC成骨和骨发育方面的研究经验的逻辑进展。

DESCRIPTION (provided by applicant): Candidate: I will begin as an Assistant Professor at the University of Michigan with a focus on burn and reconstructive surgery. I recently completed a two-year basic science post-doctoral fellowship studying basic and translational approaches in stem cell and bone biology. My long-term career goal is to achieve scientific independence, and to establish a translational research laboratory to improve diagnostic and treatment strategies for patients with burns, traumatic injuries and heterotopic ossification (HO). Environment: I work within the state-of-the-art Medical Science and Basic Science Research Buildings. My primary mentor, Dr. Wang is a researcher in burn and trauma injury, inflammation pathways and novel imaging modalities. With Dr. Wang, my advisory committee includes well-established experts in bone biology, inflammatory pathways, stem cells, mutant animal development and in vivo imaging. Research: Heterotopic ossification is a common condition seen after burn and trauma injuries. Recent evidence from in vitro and in vivo models in our laboratory suggests that burn injury enhances the osteogenic capacity of mesenchymal stem cells (MSCs) and stimulates HO formation. New mechanistic insight has revealed that burn injury may exert this effect through adenosine triphosphate (ATP) and smad-dependent Bone Morphogenetic Protein Receptor 1A (Bmpr1a) signaling. This osteogenic capacity of MSCs and HO formation is blunted when the burns are treated with an ATP hydrolyzing agent (apyrase). These findings suggest burn injury as a causative factor in HO formation and apyrase as a prevention strategy of HO. --Aim 1. Determine the mechanism of the pro-osteogenic effects of burn injury on MSC osteogenesis and heterotopic ossification. In Aim 1A, we will examine the effect of burn injury on the osteogenic capacity of mouse MSCs from the adipose and bone marrow compartments. Small molecule BMP inhibitors, in addition to the use of MSCs from Bmpr1a mutant mice will be used. In Aim 1B we will explore the role of burn injury on in vivo HO formation using our Achilles tenotomy model. We also will apply this model after global Bmp inhibition and to our Bmpr1a mutant mice to further understand the role of Bmpr1a on HO. --Aim 2: Demonstrate the anti-osteogenic effect of ATP hydrolysis on MSCs and in vivo HO formation. In Aim 2A we will optimize the delivery of the ATP hydrolyzing enzyme apyrase in our mouse burn model and MSCs will be analyzed for their osteogenic capacity. In Aim 2B, we will determine if apyrase application to the burn site can block HO formation using our Achilles tenotomy model. These results will be critical to clinical translation of local ATP hydrolysis as a prevention strategy fr HO. --Summary: This K08 proposal is designed to allow for expedient progress toward my goal of becoming an independent surgeon scientist with a focus on burn injury and heterotopic ossification. This proposal is a logical progression from my previous research experience in MSC osteogenesis and bone development.