Fibrosis is an immune-mediated process that leads to abnormal collagen deposition in different organs and it contributes to almost half of all deaths as an end result of chronic inflammation in diseases such as atherosclerosis, chronic kidney disease, and inflammatory bowel disease. Scleroderma is the prototypic fibrotic disease and causes devastating fibrosis in the skin, lungs and other organs. In the skin, it leads to debilitating contractures and in the lung, it causes progressive asphyxiation and death. Its pathogenesis is poorly understood and there are few therapies that have significant impact.
A fundamental question that drives my work is how immune cells regulate tissue fibrosis. Although there are many studies of scleroderma fibroblasts, the disease is likely mediated by hematopoietic cells, as evidenced by the development of sclerotic graft vs host disease (GvHD) after stem cell transplant, which while not the same disorder, can mimic scleroderma both clinically and histologically. To understand which immune cells are important for fibrosis, I focus on patient-based translational studies as well as basic science approaches with mouse genetics and in vitro cell cultures. To bridge the advantages of mouse studies with the use of human tissue, I am developing a humanized mouse model of scleroderma. In this model, I engraft human skin and stem cells into mice that can support the development of a human immune system. This model allows us to ask questions that wouldn’t be possible with patients, such as making additional genetic alterations or use new compounds and antibodies. All together the purpose of these studies is to understand fundamental questions about scleroderma and chronic GvHD pathogenesis in order to develop new therapeutics.
Fibrosis; Graft vs Host Disease; Scleroderma, Systemic