Program Director/Principal Investigator (Last, First, Middle): Hadjiargyrou, Michael PROJECT SUMMARY (See instructions): Cartilage is the initial tissue of the skeleton that forms during embryonic development and participates in endochondral ossification of bones during growth and fracture repair. Chondrogenesis and subsequent bone formation is a complex process that is guided by cellular events ultimately governed by genetic networks. Identifying key regulatory genes of chondrogenesis is essential in enhancing our understanding, not only of cartilage formation, but also of skeletal pathologies and repair. The main objective of this proposal is to establish a functional relationship between Mustn1 (discovered in my laboratory) and chondrogenesis by generating and characterizing Mustn1 conditional knockout (KO) mice. Previously, we showed Mustn1 to be robustly expressed in the developing skeletal system; to display differential temporal and spatial expression in proliferating chondrocytes of articular cartilage and cartilaginous fracture callus, necessary for chondrogenic proliferation and differentiation in vitro; and, when silenced, to downregulate cartilage-related genes, thus leading to severe cartilage deficits during development in vivo. We plan to extend these findings and test the hypothesis that Mustn1 is a key regulator in chondrocytes and is required for cartilage formation during embryonic development and fracture repair. To address this hypothesis, we will generate Mustn1 conditional (in cartilage) KO mice and assess its role during skeletal development and growth (Aim 1) and fracture repair (Aim 2). By examining the consequences of Mustn1 deletion in chondrocytes, its functional contribution to chondrogenesis and overall skeletal development and repair will be clearly deciphered. We are hopeful that in the future, this will enable us to address a major challenge in orthopaedic medicine, that is, cartilage regeneration necessary to repair joint surface defects arising from trauma or arthritis, as well as impaired fracture repair (i.e. delayed and nonunions). Moreover, as Mustn1 does not belong to any known class of proteins, its investigation may lead to the elucidation of a new and uncharacterized protein family and/or regulatory pathways vital to chondrogenesis. Lastly, these transgenic mice will be available and serve as useful experimental tools for many investigators working on various cellular and molecular aspects of cartilage biology. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) New York Institute of Technology (NYIT) Stony Brook University (SBU) PHS 398 (Rev. 03/16 Approved Through 10/31/2018) OMB No. 0925-0001 Page 2 Form Page 2

Public Health Relevance

(RELEVANCE) Tens of millions of humans suffer from arthritis and fractures. Therefore, augmentation of cartilage regeneration and fracture repair could substantially improve their quality of life. Our approach of exploring the role of Mustn1 will enhance our understanding of chondrogenesis and expedite the development of a line of research that will prove necessary in promoting effective cartilage regeneration and skeletal repair. Lastly, the investigation of Mustn1 may lead us into the understanding and elucidation of a new and uncharacterized protein family with a major role in cartilage biology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Winer, Karen
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New York Institute of Technology
Other Basic Sciences
Schools of Arts and Sciences
Old Westbury
United States
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