Novel Pathway and Prevention Strategy for Heterotopic Ossification

求职者：我将在密歇根大学担任助理教授，专注于烧伤和重建外科。我最近完成了一个为期两年的基础科学博士后奖学金，学习干细胞和骨生物学的基本方法和翻译方法。我的长期职业目标是实现科学独立，并建立一个转化性研究实验室，以改进烧伤、创伤和异位骨化(HO)患者的诊断和治疗策略。环境：我在最先进的医学和基础科学研究大楼内工作。我的主要导师王博士是一名研究烧伤和创伤损伤、炎症途径和新型成像方式的研究员。与王博士一起，我的顾问委员会包括在骨生物学、炎症途径、干细胞、突变动物发育和活体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情况。本实验室体外和体内模型的最新证据表明，烧伤可增强间充质干细胞(MSCs)的成骨能力，并刺激HO的形成。新的机制研究表明，烧伤可能通过三磷酸腺苷(ATP)和Smad依赖的骨形态发生蛋白受体1A(BMPR1A)信号转导发挥这种作用。当烧伤用ATP水解剂(Apyrase)处理时，MSCs和HO形成的这种成骨能力被钝化。这些发现提示烧伤是HO形成的原因之一，apyrase是HO的预防策略。目的1.确定烧伤对MSC成骨和异位成骨的促成骨作用的机制。在目标1A中，我们将检测烧伤对小鼠脂肪和骨髓间充质干细胞成骨能力的影响。小分子BMP抑制剂，除了使用来自BMPR1A突变小鼠的MSCs外，还将使用。在目标1B中，我们将使用我们的跟腱切断术模型来探索烧伤在体内HO形成中的作用。我们还将在全局BMP抑制后应用此模型，并将其应用于我们的BMPR1A突变小鼠，以进一步了解BMPR1A在HO中的作用。--目的2：证明三磷酸腺苷水解物对间充质干细胞和体内HO形成的抗骨形成作用。在目标2A中，我们将优化ATP水解酶apyrase在小鼠烧伤模型中的输送，并将分析MSCs的成骨能力。在目标2B中，我们将使用我们的跟腱切断术模型来确定在烧伤部位应用apyrase是否可以阻止HO的形成。这些结果将对临床将局部ATP水解酶转化为HO的预防策略至关重要。--总结：这份K08提案旨在让我朝着成为一名专注于烧伤和异位骨化的独立外科科学家的目标取得权宜之计。这一建议是我之前在MSC成骨和骨发育方面的研究经验的一个合乎逻辑的进步。

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.