RR&D Research Career Scientist Award Application

RR

• 批准号: 10754152
• 负责人: Melissa A Kacena
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754152
• 关键词: 2019-nCoV; ALCAM gene; Acceleration; Accidents; Accounting; Age; Aging; American; American Society of Hematology; Amputation; Analgesics; Animal Model; Applications Grants; Award; Biography; Biology; Blood; Bone Marrow; Bone Regeneration; Book Chapters; Caring; Cells; Clinic; Clinical; Clinical Trials; Collaborations; Data; Defect; Department of Defense; Development; Devices; Diabetes Mellitus; Disease; Doctor of Philosophy; Drug Targeting; Endocrinology; Equipment; Extramural Activities; Faculty; Family suidae; Fellowship; Foundations; Fracture; Funding; Future; Goals; Grant; Grant Review; Growth Factor; Health; Healthcare; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; High Fat Diet; High School Student; Histone Deacetylase; Human; Impairment; Indiana; Infection; Inflammation; Injury; Institution; Intellectual Property; International; Investigation; Journals; Leadership; Legal patent; Limb structure; Locomotion; Manuscripts; Medical; Medical Students; Medicine; Megakaryocytes; Mentors; Messenger RNA; Military Personnel; Minerals; Modeling; Modernization; Mus; Musculoskeletal; Natural regeneration; Nerve Degeneration; New Zealand; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Occupational Therapy; Open Fractures; Operative Surgical Procedures; Opioid; Orthopedic Surgery; Orthopedics; Osteoporosis; Outcome; Overdose; Overweight; Pain; Pain management; Patient-Focused Outcomes; Peer Review; Pharmaceutical Preparations; Population Projection; Postdoctoral Fellow; Productivity; Prosthesis; Publications; Publishing; Quality of life; Recovery; Regimen; Regulation; Rehabilitation therapy; Reporting; Research; Research Activity; Research Personnel; Review Committee; Risk; Roentgen Rays; Role; SIRT1 gene; Scientist; Seminal; Services; Sheep; Side; Site; Societies; Soldier; Space Flight; Study Section; Surgeon; System; Testing; Therapeutic Agents; Thrombopoietin; Time; Tissues; Training; Translating; Trauma; United States National Institutes of Health; Universities; Veterans; War; Weight-Bearing state; Wheelchairs; Work; active duty; aged; angiogenesis; animal efficacy; bone; bone fracture repair; bone healing; bone loss; bone mass; care burden; career; diabetic; editorial; fighting; frontier; functional outcomes; graduate student; healing; human old age (65+); improved; in vivo imaging system; invention; lectures; limb injury; medical schools; meetings; member; military veteran; novel; novel therapeutic intervention; older patient; opioid epidemic; pain behavior; pain reduction; peptidomimetics; pharmacologic; prescription opioid; programs; reconstruction; recruit; repaired; severe injury; skeletal; stem; stem cell function; undergraduate student; wounded soldier

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.

我的研究计划的主要目标是识别和测试新的治疗方法以改进和 加速骨折愈合和整体患者预后。这包括改善体重，运动， 和活动，同时减轻相关的疼痛和炎症。在我目前的VA资助研究中，我们是 试图确定Sirtuin-1（SIRT1，NAD+ III级Hisstone脱乙酰基酶）激活剂如何改变断裂愈合 结果。我们开始研究SIRT1作为目标，因为我们的初步数据表明SIRT1的mRNA水平是 骨折愈合期间稳健地升高。我们知道骨折愈合会因年龄，骨质流失而受损 炎症和神经变性，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破裂结果。那是一个重要的目标 我们的研究是将我们的发现转化为诊所。考虑到这一点，我们成功获得了一项专利 （16/392,246，2019年4月23日），并申请了第二份专利（63/153,297，2021年2月24日）。第二个 专利申请包括DRS。菲利普·洛（Philip Low）和杰弗里·尼尔森（Jeffery Nielsen）担任共同发明家（也是我们当前的合作者 VA功绩奖）是医学化学家。在他们的帮助下，我们开发了一个针对的新骨折 SRT1720药物，我们正在VA优异研究中进行研究。值得注意的是，劳特博士的15种药物 研究已进入人类临床试验。重要的是，我们还与 VA研究者，弗莱彻·怀特（Fletcher White）博士，具有运动，疼痛和炎症专业知识的神经科学家 分析。我们团队将一起研究骨折靶向对SIRT1的药物激活 SRT1720允许改善骨折愈合，同时减少疼痛行为。 由3个PI/MPI NIH R01和内部，基金会和培训奖的其他研究重点关注 骨髓微环境及其对骨折愈合，骨骼量和造血的调节。目标 NIH R01 AG060621的作用是了解血管生成疗法的机制 断裂愈合。 NIH R01 DK118782的目标是了解骨瘤和骨瘤的机制 巨核细胞调节造血。 NIH R01 DK108342的目标是检查CD166如何调节 造血干细胞功能和造血生态位。飞行员基金和NIH F31 AG077931博士 SARS-COV-2感染后骨质流失的研究金基金调查。这些研究有 对帮助退伍军人的康复和改善生活质量的重大影响。 我的实验室非常有效，有52个数据驱动的手稿和17篇评论文章/章节发表了 自2018年以来。在此期间，我在国家/国际场所进行了21次讲座，其中包括邀请 2019年，澳大利亚和新西兰骨与矿物协会会议的著名发言人。 在过去的15年中，持续的壁外资金使我们能够实现研究目标。 我还广泛参与了心理初级教师，博士后研究员，临床居民， 研究生，医学生，本科生和高中生已有20多年 （> 100 menees）。我曾在国家和国际级别的众多赠款审查委员会任职 包括作为NIH的常任成员，骨骼生物学发展与疾病（SBDD）研究部分 并将在2023年开始审查VA优异奖。 《骨科研究与JBMR Plus》杂志；作为内分泌学边界的客座编辑；部分 当前骨质疏松报告的编辑；并且是当前骨质疏松报告的主编。我也有 在几个机构/社会中被提名并当选为领导角色。目前，我是恶习 IUSM骨科手术系研究主席，是当选成员 美国骨与矿物研究协会委员会。这些研究，心理，领导和 服务活动突出了我对肌肉骨骼领域的研究活动的重要性和认可。