Probing skeletal diseases. Human beings are 60% water; so what keeps us from slipping off our bones and into a puddle on the floor? The short answer is collagen, a chainlike molecule that helps prevent joints from pulling apart and teeth from getting loose. Breakdowns in the formation and organization of collagen cause a number of diseases, including osteoarthritis. The Olsen lab is trying to identify and sequence the genes that help to create different types of collagen. Mice that are missing the gene for one type, collagen IX, seem predisposed to suffer from a disease much like human osteoarthritis. This exciting indication of a genetic cause of arthritis, which the lab is investigating further, creates an even stronger motivation to learn the genetic basis for diseases involving other types of collagen and other proteins in the extracellular matrix that surrounds and connects cells. In addition, the lab is identifying gene mutations that are responsible for defects in skeletal patterns in developing limbs and growth of bones during development. In a recent discovery the inherited disorder synpolydactyly, a condition characterized by extra fingers and variable fusion of fingers, was found to be caused by mutations in a gene, HOXD13, that controls the activity of many other genes which are important for cell growth and differentiation during limb development. Cleidocranial dysplasia, a condition characterized by delayed suture ossification in the skull, supernumerary teeth and missing clavicles, was found to be caused by mutations in the gene CBFA1, a transcription factor needed for cells to become bone cells.
Probing vascular disorders. Blood vessels are tubes of endothelial cells surrounded by layers of smooth muscle cells and connective tissue proteins. During development this complex structure forms as a result of biochemical signals between endothelial cells and smooth muscle cells. Sometimes this biochemical communication fails and abnormal blood vessels form. By analyzing gene mutations causing such vascular abnormalities, much can be learned about the signals that are necessary for normal blood vessel development. In addition, identification of genes responsible for inherited vascular malformations provides a basis for development of rational therapies in the clinical treatment of vascular disorders. One by one, the Olsen lab is trying to identify the genes that cause several forms of venous malformations and determine the precise mutations in these genes.
Projects
Our laboratory studies tissue and organ morphogenesis. Work in the laboratory is currently directed at four project areas.
In the first project we study skeletal morphogenesis and growth. We are interested in genes that control differentiation of mesenchymal cells to chondrocytes and osteoblasts, the control of spatial patterns of mesenchymal condensations during skeletal development and tooth formation, the molecular mechanisms controlling the formation of ossification centers, and the regulation of proliferation and differentiation of chondrocytes in growth plates. In addition to using transgenic mice in studies of specific genes, we make extensive use of genetic approaches in mice and humans. This includes mapping of inherited disorders, gene identification and mutation detection.
In the second project we investigate the molecular basis for vascular morphogenesis, using a combination of human genetics and studies of cells in culture. In addition, we use gene targeting to generate mice with inactivated alleles for collagens that are expressed in vascular walls.
In the third project we are studying genetic risk factors for osteoarthritis in humans. One approach involves identification of mutations responsible for early-onset osteoarthritis as part of inherited osteochondrodysplasias; in other studies we are screening a population of patients with osteoarthritis for mutations in candidate genes.
In the fourth project we are studying the molecular mechanisms that lead to neoformation of dermal tissue in fibrotic diseases using keloid formation as a model. Our aims are 1) to determine genes that cause keloids in families with heritable keloid formation, 2) to identify mutations in these genes and 3) to study their function and the biological consequences of mutations. We chose a genetic approach to detect one disease gene locus in a large family with keloids. The disease gene interval has been reduced to already less than one Megabase and candidate genes are being evaluated.