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.

PROJECT NARRATIVE One in 4 Veterans receiving VA care is diabetic, and over 70% are overweight or obese and at risk of developing diabetes. Additionally, according to the Veteran Population Projection Model 2018, there are greater than 6 million Veterans over the age of 65. Elderly patients, as well as those with diabetes, tend to have poor fracture healing, and increases in fracture healing complications. We have identified new bone healing agents that may not only improve bone healing and functional outcomes, but may also decrease the associated pain. The latter, could replace the necessity of opioids for pain management and serve as an important step in fighting the current opioid crisis.