RR&D Research Career Scientist Award Application

我的研究计划的一个主要目标是确定和测试新的治疗方法，以改善和 加速骨折愈合和整体患者转归。这包括改善负重，运动， 和活动，同时减少相关的疼痛和炎症。在我目前由退伍军人管理局资助的研究中，我们 试图确定Sirtuin-1(Sirt1，一种NAD+III类组蛋白去乙酰基酶)激活剂如何改变骨折愈合 结果。我们开始检查Sirt1作为目标，因为我们的初步数据显示Sirt1的mRNA水平是 在骨折愈合过程中强劲地升高。我们知道骨折愈合会随着年龄、骨质流失而受损， 炎症和神经退行性变，并意识到Sirt1改善了所有这些条件。 我们的最终目标是改善退伍军人和平民的骨折结果。因此，一个重要的目标是 我们的研究是将我们的发现转化为临床。考虑到这一点，我们成功地获得了一项专利 (2019年4月23日16/392,246)，并已申请第二项专利(63/153,297,2021年2月24日)。第二 专利申请包括菲利普·洛博士和杰弗里·尼尔森博士作为共同发明人(也是我们目前 荣誉奖)，他们都是药物化学家。在他们的帮助下，我们开发了一种新的靶向骨折 SRT1720药物，我们正在VA Merit研究中对其进行调查。值得注意的是，15种药物源于刘特佐博士的 研究已经进入人体临床试验。重要的是，我们还与 弗吉尼亚州研究员弗莱彻·怀特博士是一位在运动、疼痛和炎症方面拥有专业知识的神经科学家 分析。我们的团队将共同研究通过骨折靶向对Sirt1进行药理学激活 SRT1720可改善骨折愈合，同时减少疼痛行为。 由3个PI/MPI NIH R01以及内部、基金会和培训奖资助的其他研究侧重于 骨髓微环境及其对骨折愈合、骨量和造血的调节。目标是 NIH R01 AG060621的目的是了解血管生成疗法改善衰老的机制 骨折愈合。NIH R01 DK118782的目标是了解骨瘤和骨肿瘤的机制 巨核细胞调节造血。NIH R01 DK108342的目标是研究CD166如何调节 造血干细胞功能和造血生态位。试点基金和NIH F31 AG077931博士学位 SARS-CoV-2感染后骨丢失的研究。这些研究已经 对帮助退伍军人康复和提高他们的生活质量具有重要意义。 我的实验室非常有成效，发表了52篇数据驱动的手稿和17篇评论文章/章节 自2018年以来。在此期间，我已在国内/国际场合进行了21次演讲，包括作为 澳大利亚和新西兰骨与矿物协会2019年会议的受人尊敬的发言人。 在过去的15年里，持续不断的外部资金使我们能够实现我们的研究目标。 我还广泛参与指导初级教员、博士后研究员、临床住院医师、 研究生、医学生、本科生、高中生20多年 (&gt；100名学员)。我曾在许多国家和国际层面的拨款审查委员会任职。 包括作为NIH骨骼生物学发育和疾病(SBDD)研究科的常任成员 并将于2023年开始审查退伍军人事务部荣誉奖。我曾担任/正在担任编辑评审委员会的成员 整形外科研究杂志和JBMR Plus；作为内分泌学前沿的客座编辑； 《最新骨质疏松症报告》编辑；我是《最新骨质疏松症报告》主编。我也有过 被提名并当选为几个机构/社会的领导职务。目前，我是副总统 我是IUSM整形外科研究部主任，也是 美国骨骼和矿物研究学会理事会。这些研究、指导、领导力和 服务活动突出了我的研究活动对肌肉骨骼领域的意义和认可。

A primary goal of my research program is to identify and test new therapeutic approaches to improve and accelerate fracture healing and overall patient outcomes. This includes improving weightbearing, locomotion, and activity, while decreasing the associated pain and inflammation. In my current VA funded studies, we are seeking to determine how Sirtuin-1 (Sirt1, an NAD+ class III histone deacetylase) activators alter fracture healing outcomes. We began examining Sirt1 as a target as our preliminary data showed that mRNA levels of Sirt1 are robustly elevated during fracture healing. We knew that fracture healing is impaired with age, bone loss, inflammation, and with neurodegeneration, and realized that Sirt1 improves all of these conditions. Our ultimate goal is to improve fracture outcomes for Veterans and civilians. Thus, an important objective of our studies is to translate our findings to the clinic. With this in mind, we have successfully obtained one patent (16/392,246, April 23, 2019) and have applied for a second patent (63/153,297, February 24, 2021). The second patent application includes Drs. Philip Low and Jeffery Nielsen as co-Inventors (also collaborators on our current VA Merit award) who are medicinal chemists. With their assistance, we developed a new fracture targeted SRT1720 drug, which we are investigating in our VA Merit studies. Notably, 15 drugs stemming from Dr. Low’s research have entered human clinical trials. Importantly, we have also developed an important collaboration with VA investigator, Dr. Fletcher White, a neuroscientist with expertise in locomotion, pain, and inflammation analyses. Together, our team will investigate whether pharmacological activation of Sirt1 by fracture targeting SRT1720 allows for improved fracture healing, while reducing pain behaviors. Additional studies funded by 3 PI/mPI NIH R01s and internal, foundation and training awards focus on the bone marrow microenvironment and its regulation of fracture healing, bone mass, and hematopoiesis. The goal of NIH R01 AG060621 is to understand the mechanisms by which angiogeneic therapies can improve aged fracture healing. The goal of NIH R01 DK118782 is to understand the mechanisms by which osteomacs and megakaryocytes regulate hematopoiesis. The goal of NIH R01 DK108342 is to examine how CD166 regulates hematopoietic stem cell function and the hematopoietic niche. Pilot funds and an NIH F31 AG077931 PhD fellowship fund investigations on the bone loss following infection with SARS-CoV-2. These studies have significant implications to aiding in rehabilitation of Veterans and improving their quality of life. My lab has been very productive with 52 data driven manuscripts and 17 review articles/chapters published since 2018. During this time, I have given 21 lectures at national/international venues, including an invitation as an Esteemed Speaker for the Australian and New Zealand Bone and Mineral Society meeting in 2019. Continuous extramural funding for the past 15 years has enabled us to achieve our research goals. I have also been extensively involved with mentoring junior faculty, post-doctoral fellows, clinical residents, graduate students, medical students, undergraduate students, and high school students for more than 20 years (>100 mentees). I have served on numerous grant review committees at national and international levels including as a permanent member of the NIH, Skeletal Biology Development and Disease (SBDD) Study Section and will begin reviewing VA Merit Awards in 2023. I have served/am serving on the Editorial Review Board for the Journal of Orthopaedic Research and JBMR Plus; as a Guest Editor for Frontiers in Endocrinology; section editor for Current Osteoporosis Reports; and am Editor-in-Chief for Current Osteoporosis Reports. I have also been nominated and elected into leadership roles within several institutions/societies. Currently, I am the Vice Chair for Research for the Department of Orthopaedic Surgery at IUSM and am an elected member of the Council for the American Society for Bone and Mineral Research. These research, mentoring, leadership, and service activities highlight the significance and recognition of my research activities to the musculoskeletal field.