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Collagenous proteins play a pivotal role in forming the architecture of connective tissues and organs, including bone, tendon, cartilage, skin, peripheral nerves, liver, lung, and others. At the macro-level these proteins provide mechanical strength to all tissues and organs, and at the molecular-level they provide crucial signaling to cells. While in physiological conditions the homeostasis of collagens facilitates normal functions of tissues and organs, aberrations of these proteins cause devastating effects.
The Fertala laboratory studies fibrotic diseases that develop due to injury of orthopedically-relevant tissues, including joint capsule, tendon, ligament, peripheral nerve, and others. In collaboration with clinical partners, they also study lung fibrosis and ocular fibrosis. In addition to studies on pathomechanisms of fibrotic response to tissue injury, the Fertala laboratory develops novel anti-fibrotic approaches that target extracellular processes of scar formation.
The Fertala laboratory also studies heritable disorders of connective tissue associated with mutations in collagen genes. The main focus of these studies are dysplasias that alter skeletal development and growth.
Furthermore, the Fertala group participates in developing recombinant collagen-like proteins for potential applications in tissue engineering and drug delivery.
Preventing Excessive Scar Formation
While scar formation is a part of the natural healing process, excessive scarring is a hallmark of fibrosis. The central goal of this project is to develop novel approaches to limit fibrotic scarring in orthopedically-relevant tissues. The research group led by Dr. Fertala has identified collagen fibrillogenesis as a valid target to limit excessive formation of collagen-rich tissue deposits. The group has developed and patented a monoclonal antibody that inhibits collagen-collagen interaction that drives the formation of collagen fibrils, a primary component of scar tissue. Employing a clinically-relevant animal model, the group has demonstrated the utility of their anti-fibrotic approach to reduce post-traumatic joint stiffness caused due to excessive scarring of joint tissues. Furthermore, the group demonstrated the anti-fibrotic potential of the antibody in animal models of pulmonary fibrosis and keloid.
The group carries out their research under the auspices of the Scientific Consortium for Arthrofibrosis Research (SCAR), which includes a group of dedicated orthopedic surgeons from the Rothman Orthopaedic Institute. The group’s interests include post-traumatic joint stiffness, Dupuytren’s contracture, and scarring of peripheral nerves.
Beyond the orthopedic targets, the Fertala group conducts collaborative research on limiting fibrotic processes occurring in the lung and the eye.
Skeletal Dysplasias Caused By Mutations In Collagen Genes
Brittle bones and alterations of growth define heritable disorders of skeletal tissues caused by mutations in collagen genes. The Fertala laboratory focuses on diseases associated with mutations in collagen II, the pivotal component of the developing skeleton and mature cartilage. Utilizing an experimental system to express collagen II mutants, Dr. Fertala’s team studied the molecular basis of the genotype-phenotype relation. These studies indicated the significant role endoplasmic reticulum (ER) stress plays in pathomechanism of spondyloepiphyseal dysplasia (SED). The group has demonstrated that applying chemical chaperones reduces ER stress and partially restores crucial functions of cells that harbor mutant collagen II.
More recently, Dr. Fertala and his collaborators developed a transgenic mouse model to study the feasibility of treatment of SED. They focused on defining the time window during which any potential treatment must be applied to be successful. Results of the studies demonstrated that treatments that reduce the expression of mutant alleles are only valid when applied in utero during early stages of skeletal development. In contrast, treatments to reduce the expression of mutant alleles applied late in embryonic development or during the postnatal stages do not improve skeletal growth. These studies provide valuable guidance for designing future therapies to treat patients that harbor mutations in collagen genes.