Tissue fibrosis is a feature of virtually all diseases of chronic organ failure. In many cases, fibrosis is the causative factor leading to morbidity and mortality in these diseases, such as in liver cirrhosis or Idiopathic Pulmonary Fibrosis. Consequently, fibrosis contributes to a very large public health burden and expenditure of healthcare resources. Yet, there remain significant knowledge gaps in the basic biology of fibrosis and there are few effective therapies for such diseases. This presents a large unmet medical need and is the main focus of our laboratory.
Fibrosis is usually defined as the excess accumulation of extracellular matrix that replaces normal tissue architecture. Yet, this can actually be part of the physiologic process of wound healing or organ injury in general. The distinction between normal wound healing and pathological fibrosis is the persistence of fibrosis. The biology that underlies whether fibrosis resolves or persists still remains vexingly opaque. It is this area which we study in particular with the goal to better understand the resolution of fibrosis through several complementary approaches. Current active projects in the laboratory include:
- Studies of age-related impaired resolution of fibrosis: A key insight in the study of fibrosis resolution was that aged individuals cannot resolve fibrosis after a given injury that produces resolution in a developing or young individual. In recent work, we have shown that this phenotype is associated with age-related reduction in collagen turnover pathways, including the cell-based endocytic machinery for collagen degradation. We use multi-omic approaches to study the mechanistic basis for these age-related changes and the roles they play in normal aging and fibrotic disease.
- High throughput approaches to characterize novel extracellular matrix turnover machinery: We have developed tools to utilize genome-wide, high-throughput, pooled CRISPR-based phenotypic screens to ascertain novel molecules involved in ECM metabolism. These unbiased approaches have the potential to generate new therapeutic targets as well as to identify novel basic biology.
- Creation of orthogonal and novel models of fibrosis: Essentially all common fibrosis models involve both matrix production and degradation concurrently and thus convolute the study of these underlying biological processes. We are developing tools and models to try to better isolate these underlying processes to unpack the complex biology of ECM turnover.