Grant: Operating Grant

Cells are connected to each other by an array of proteins known as connective tissue that play an important role in optimal cell function. When connective tissue fails, a multitude of disease states can ensue. From genetic disorders and aging to orthopaedic impairments, health care costs and quality of life are severely impacted by dysfunction of connective tissue. More research, both basic and applied, is urgently needed to better understand the specific steps that result in connective tissue failure and how these conditions can be better treated. This project aims to examine some of the molecular mechanisms involved in connective tissue related disease. Connective tissue contains very fine fiber-like strands, called microfibrils, that play an important role in both structural support of the tissue and the way cells function. If the fundamental composition of these microfibrils become altered, or mutated, it gives rise to severe and sometimes life threatening complications that can affect blood vessels, bones and eyes. Correct formation and function of these fibers is essential, since these aspects are frequently disturbed in these disorders. The goal of this project is to investigate the molecular mechanisms involved in the formation and function of these microfibrils in normal and in disease situations using cell biological, biochemical and animal approaches. We intend to determine the significance of specific active regions in the major protein of microfibrils (fibrillin). We will determine the role of an important protein (fibronectin) which guides the formation of microfibrils. The effects of mutations in the fibrillin protein on its ability to function and on cell behavior will be studied. It is expected that the information obtained from this project will not only contribute to the fundamental understanding how these fibers work, but will also help in the development of new diagnostic and therapeutic strategies for the entire group of these disorders.