PROJECT SUMMARY Osteoporosis, or low bone mineral density, is a common disease of aging resulting in 2.3 million fractures every year with an annual societal cost of over $57 billion. First-line treatments for osteoporosis preserve bone mineral density by inhibiting resorption in osteoclasts, resulting in an overall decrease in bone resorption and turnover. The side effects associated with anti-resorptive therapies commonly decrease patient compliance with treatment recommendations. The few anabolic therapeutics available facilitate bone formation in the osteoblast, but are reserved for high-risk patients due to their cost, subcutaneous administration route, and lack of long-term safety data. The identification of new therapeutic targets will help facilitate the development of well-tolerated alternative therapies that build high quality bone. There remain significant gaps in our knowledge of proteins regulating bone mineral density, through both bone formation and resorption in the osteoblast and osteoclast, respectively. With a critical need for accessible anabolic bone therapies, a greater understanding of signaling pathways regulating osteoblast differentiation and mineralization will help in identification of new therapeutic targets facilitating bone formation. DOCK7 is a guanine nucleotide exchange factor known to regulate the Rho family of small GTPases. GTPases are molecular switches that activate cell signaling pathways, controlling almost all cellular processes. This proposal presents exciting preliminary data demonstrating that both global loss of DOCK7 and conditional deletion of DOCK7 in osteoblast progenitor cells leads to low bone mineral density in vivo and decreases mineralization in vitro. These data suggest that DOCK7 is essential for the development of normal bone mineral density and critical in regulating bone formation directly in the osteoblast. Furthermore, global loss of DOCK7 results in a striking increase in osteoclast numbers, highlighting a role for DOCK7 in bone resorption. The experiments proposed here will examine the mechanism by which DOCK7 controls bone metabolism in both the osteoblast and osteoclast, exploring the novel molecular network of factors regulating bone remodeling using a conditional deletion mouse model. Specific Aim 1 will examine the role of DOCK7 in mediating signals from extracellular ligands critical to osteoblast function through small GTPases such as RAC1. We will also utilize an unbiased approach designed to identify novel DOCK7 binding partners and regulatory networks associated with bone formation by mass spectrometry and RNA sequencing. Specific Aim 2 will characterize the role of DOCK7 in bone resorption in vivo and in vitro in osteoclast culture. This proposal will use innovative approaches to explore mechanisms by which DOCK7 influences bone metabolism in order to establish a set of novel factors regulating bone mineral density. These factors will be the subject of future work explorin...