Individual Predoctoral Dental Scientist Fellowship

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DESCRIPTION (provided by applicant): Temporomandibular joint osteoarthritis (TMJ OA) is one of the most predominant types of TMJ disorders, yet little is known about the molecular mechanisms underlying the disease. Genetic animal models can be used as scientific tools to investigate the mechanistic basis for temporomandibular joint osteoarthritis (TMJ OA). Our group has generated one such mouse model where mice deficient in two extracellular matrix (ECM) proteins, biglycan (BGN) and fibromodulin (FMOD) develop accelerated TMJ OA. We propose to study the cellular mechanisms contributing to the early onset of the disease before permanent destruction of the cartilage tissue occurs. BGN and FMOD are members of the small leucine-rich proteoglycan family and can modulate transforming growth factor-beta1 activity (TGF-beta1). TGF-beta1 is a critical growth factor for regulating and sustaining cartilage homeostasis. Our working hypothesis is that bgn/fmod deficiency alters chondrocyte growth, differentiation, and ECM production that might occur through the dysregulation of TGF-beta1 activity. To test our hypothesis, the following specific aims have been formulated: 1) examine the progressive histopathological changes, extracellular matrix composition and cellular changes including cell proliferation and cell apoptosis in the TMJ cartilage of wildtype and bgn/fmod deficient mice; and 2) determine the early mechanistic role of TGF-beta1 in regulating extracellular matrix composition (ECM) and altered cell processes in the TMJ cartilage of wildtype (WT) and bgn/fmod deficient mice (DKO). A comprehensive in vivo analysis of our TMJ OA model as the disease progresses will provide clues as to what factors and cellular events are changed in the DKO TMJ. Our characterization of the DKO TMJ will include the examination of the expression of ECM proteins that are critical for cartilage maintenance by immunohistochemistry. We will also examine cellular proliferation and cellular apoptosis in order to detect if these cellular processes are altered in the DKO. We will use an ex vivo organ culture system and primary cell cultures to test the effects of exogenous TGF-beta1 on regulating the ECM composition and cellular processes we investigate in our in vivo animal model. PUBLIC HEALTH RELAVANCE: Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease that leads to permanent tissue destruction, joint dysfunction, and disabling pain. We have generated mice deficient in two proteins found in the TMJ, bigylcan and fibromodulin, that develop accelerated TMJ OA. Our goal is to use this animal model as a scientific tool to investigate the early cellular events contributing to the onset of TMJ OA to help improve effective diagnostic tests and therapies.