Novel Pathway and Prevention Strategy for Heterotopic Ossification

异位骨化的新途径和预防策略

• 批准号: 9321145
• 负责人: Benjamin Levi
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321145
• 关键词: Acute; Adenosine; Adenosine Triphosphate; Adipocytes; Adipose tissue; Advisory Committees; Animals; Apyrase; Articular Range of Motion; Basic Science; Biology; Bone Development; Bone Diseases; Bone Marrow; Burn Trauma; Burn injury; Complication; Contracture; Cyclic AMP; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Distant; Dorsal; Early Diagnosis; Environment; Enzymes; Excision; Fascia; Fatty acid glycerol esters; Fellowship; Foundations; Goals; Heterotopic Ossification; Hydrolysis; Image; In Vitro; Inflammation; Inflammatory; Injury; Joints; Knockout Mice; Laboratories; Laboratory Research; Limb structure; Mediating; Medical; Mentors; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methods; Michigan; Minerals; Modeling; Mus; Muscle; Musculoskeletal Diseases; Mutant Strains Mice; Operative Surgical Procedures; Orthopedic Procedures; Osteogenesis; Pain; Pathway interactions; Patients; Postdoctoral Fellow; Prevention; Prevention strategy; Process; Protocols documentation; Publishing; Reconstructive Surgical Procedures; Research; Research Personnel; Residual state; Role; Science; Scientist; Signal Pathway; Signal Transduction; Site; Skin; Stem cells; Surgeon; Tendon structure; Therapeutic; Time; Translational Research; Traumatic injury; Treatment Protocols; Universities; Work; bone; bone morphogenetic protein receptors; career; cell type; clinical translation; combat; design; experience; extracellular; imaging modality; improved; in vivo; in vivo Model; in vivo imaging; inhibitor/antagonist; innovation; insight; member; microCT; mouse model; multipotent cell; mutant; novel; novel diagnostics; operation; osteogenic; prevent; professor; prophylactic; public health relevance; receptor; small molecule; soft tissue; translational approach; treatment strategy

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.

描述（由申请人提供）：候选人：我将首先在密歇根大学担任助理教授，重点是烧伤和重建手术。我最近完成了一项为期两年的基础科学博士后研究金，研究了干细胞和骨骼生物学中的基本和翻译方法。我的长期职业目标是实现科学独立性，并建立转化研究实验室，以改善烧伤，创伤性伤害和异位骨化骨化（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建筑中工作。我的主要导师Wang博士是烧伤和创伤损伤，炎症途径和新型成像方式的研究人员。与Wang博士一起，我的咨询委员会包括骨骼生物学，炎症途径，干细胞，突变动物发育和体内成像方面的完善专家。研究：异位骨化是在烧伤和创伤伤害后看到的常见疾病。我们实验室中体外和体内模型的最新证据表明，烧伤损伤增强了间质干细胞（MSC）的成骨能力，并刺激HO形成。新的机械洞察力表明，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（BMPR1A）信号传导发挥这种作用。当用ATP水解剂（Apyrase）处理燃烧时，MSC和HO形成的成骨能力被钝化。这些发现表明，烧伤是HO形成和Apyrase作为HO的预防策略的病因。 -aim 1。确定烧伤损伤对MSC成骨和异位骨化的促稳态作用的机制。在AIM 1A中，我们将研究烧伤损伤对脂肪和骨髓室中小鼠MSC的成骨能力的影响。除了使用BMPR1A突变小鼠的MSC外，还将使用小分子BMP抑制剂。在AIM 1B中，我们将使用跟腱术模型探索烧伤损伤对体内形成的作用。我们还将在全球BMP抑制和我们的BMPR1A突变小鼠之后应用该模型，以进一步了解BMPR1A在HO中的作用。 -aim 2：证明ATP水解对MSC和体内HO形成的抗肌生成作用。在AIM 2A中，我们将优化在小鼠燃烧模型中的ATP水解酶Apyrase的递送，并将以其成骨功能分析MSC。在AIM 2B中，我们将确定在燃烧位点应用APYRASE是否可以使用我们的跟腱术模型阻止HO形成。这些结果对于局部ATP水解作为预防策略的临床翻译至关重要。 - 夏季：该K08提案旨在使我成为一名独立外科医生科学家的目标，以烧伤和异位骨化为目标。该建议是我以前在MSC成骨和骨骼发育方面的研究经验的逻辑发展。

项目成果

Photoactivated miR-148b-nanoparticle conjugates improve closure of critical size mouse calvarial defects.

• DOI: 10.1016/j.actbio.2014.10.010
• 发表时间: 2015-01
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Qureshi, Ammar T.;Doyle, Andrew;Chen, Cong;Coulon, Diana;Dasa, Vinod;Del Piero, Fabio;Levi, Benjamin;Monroe, W. Todd;Gimble, Jeffrey M.;Hayes, Daniel J.
• 通讯作者: Hayes, Daniel J.

The potential roles for adipose tissue in peripheral nerve regeneration.

• DOI: 10.1002/micr.22480
• 发表时间: 2016-01
• 期刊: MICROSURGERY
• 影响因子: 2.1
• 作者: Walocko, Frances M.;Khouri, Roger K., Jr.;Urbanchek, Melanie G.;Levi, Benjamin;Cederna, Paul S.
• 通讯作者: Cederna, Paul S.

Characterization of Heterotopic Ossification Using Radiographic Imaging: Evidence for a Paradigm Shift.

• DOI: 10.1371/journal.pone.0141432
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Brownley RC;Agarwal S;Loder S;Eboda O;Li J;Peterson J;Hwang C;Breuler C;Kaartinen V;Zhou B;Mishina Y;Levi B
• 通讯作者: Levi B

Heterotopic Ossification and Hypertrophic Scars.

• DOI: 10.1016/j.cps.2017.05.006
• 发表时间: 2017-10
• 期刊: Clinics in plastic surgery
• 影响因子: 2.3
• 作者: Agarwal S;Sorkin M;Levi B
• 通讯作者: Levi B

Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

氧雄龙与烧伤后异位骨化可能关联的调查。

• DOI: 10.1093/jbcr/irz063
• 发表时间: 2019
• 期刊: Journal of burn care & research : official publication of the American Burn Association
• 作者: Thorpe,CatherineR;UcerOzgurel,Serra;Simko,LauraC;Goldstein,Richard;Grant,GabrielleG;Pagani,Chase;Hwang,Charles;Vasquez,Kaetlin;Sorkin,Michael;Vaishampayan,Anita;Goverman,Jeremy;Sheridan,RobertL;Friedstat,Jonathan;Schulz,Joh
• 通讯作者: Schulz,Joh