Christopher L. Mendias, Ph.D. - US grants

DESCRIPTION (provided by applicant): Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that lead to tendinopathies and to translate these studies to the clinic. Tendon diseases can be painful, debilitating and significantly detract from the quality of one's life. Much of what we know about tendon fibroblast cell biology comes from in vitro cell culture studies or descriptive histological studies of diseased and healthy tissue. There has been a lack of in vivo, mechanism driven studies that combine contemporary molecular biology and genetics with precise tissue mechanics and functional measures. The long-term goal of this project is to better understand tendon fibroblast biology in the context of injury and disease, and to improve the treatment of tendinopathies. For many tissues in the body, the genes that control embryonic tissue development are also important in the repair and regeneration of adult tissues. Scleraxis is a bHLH transcription factor that is critical for the embryonic development of limb tendons, but little is known about scleraxis function in adult tendons. Our overall hypotheses are that scleraxis is important for the adaptation of tendons to mechanical loading, scleraxis is regulated by TGF-? and IGF-1 signaling pathways, and that dysregulation of scleraxis is a central factor in the development of tendinosis. These hypotheses are rigorously tested in three Specific Aims that use a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in adult wild type mice (ScxWT), adult transgenic mice with a postnatal inducible knockdown of scleraxis (ScxKD), and in cultured primary tendon fibroblast cells from humans and mice. These studies will provide important insight into adult tendon fibroblast physiology, and lay the groundwork for future translational studies focused on scleraxis to improve the treatment of patients suffering from tendinopathies.

DESCRIPTION (provided by applicant): Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that lead to tendinopathies and to translate these studies to the clinic. Tendon diseases can be painful, debilitating and significantly detract from the quality of one's life. Much of what we know about tendon fibroblast cell biology comes from in vitro cell culture studies or descriptive histological studies of diseased and healthy tissue. There has been a lack of in vivo, mechanism driven studies that combine contemporary molecular biology and genetics with precise tissue mechanics and functional measures. The long-term goal of this project is to better understand tendon fibroblast biology in the context of injury and disease, and to improve the treatment of tendinopathies. For many tissues in the body, the genes that control embryonic tissue development are also important in the repair and regeneration of adult tissues. Scleraxis is a bHLH transcription factor that is critical for the embryonic development of limb tendons, but little is known about scleraxis function in adult tendons. Our overall hypotheses are that scleraxis is important for the adaptation of tendons to mechanical loading, scleraxis is regulated by TGF-ß and IGF-1 signaling pathways, and that dysregulation of scleraxis is a central factor in the development of tendinosis. These hypotheses are rigorously tested in three Specific Aims that use a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in adult wild type mice (ScxWT), adult transgenic mice with a postnatal inducible knockdown of scleraxis (ScxKD), and in cultured primary tendon fibroblast cells from humans and mice. These studies will provide important insight into adult tendon fibroblast physiology, and lay the groundwork for future translational studies focused on scleraxis to improve the treatment of patients suffering from tendinopathies.

Abstract Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that regulate tendon growth, and to apply this knowledge to the treatment of tendinopathies and tendon injuries. Tenocytes are the major cell population in tendon. They are terminally differentiated cells which play important roles in tendon extracellular matrix (ECM) growth and remodeling. Recent work from our lab and others has identified a population of CD146+ pericytes which exist in the vasculature that directly surrounds tendon tissue. These pericytes appear able to migrate to sites of tendon growth or injury, differentiate into tenocytes, and contribute to the formation of new tendon extracellular matrix. The discovery of this new stem cell population is exciting, as it could directly lead to improved treatments for tendon disorders. Little is known about the factors that regulate the activity of these cells. Using a combination of molecular genetics, tissue mechanics, and bioinformatics techniques, our goal is to gain a greater understanding of how tenocytes respond to mechanical growth signals, and relay this information to pericytes. Our working hypothesis is that mechanical loading causes tenocytes to release factors that activate pericytes in the vasculature, which then migrate into the tendon extracellular matrix and differentiate into tenocytes. These studies will provide important insight into adult tenocyte and tendon stem cell biology, and lay the groundwork for future translational studies to improve the treatment of tendinopathies and tendon injuries.