Our research focuses on the regulatory processes that construct, maintain and repair mammalian organ systems with a principal focus on the central nervous system, skeleton and kidney.
Generation and Repair of the Kidney
The mammalian kidney plays a central role in controlling the environment for all the body’s systems, regulating blood pressure and blood composition, and removal of waste from metabolic processes. The functional unit is a nephron: up to one million nephrons are formed in the human kidney during fetal life when the supply of nephron stem/progenitor cells is exhausted. Consequently, repair of kidney damage is quite different from that of many other organ systems where stem cells remain in place throughout life. Our research on the developing kidney focuses on identifying the regulatory processes that maintain, expand and differentiate kidney stem cells to the mature cell types of the functional kidney. In the adult, we are identifying the cellular and molecular mechanisms at play in repairing damage on acute injury. These lines of research will enable complimentary strategies to treat kidney injury and disease.
Specification of the Mammalian Skeletal SystemCartilage and bone forming cells, chondrocytes and osteoblasts, respectively, share a common origin from a less specialized progenitor cell type. DNA regulatory factors and signaling pathways that govern their activity control the ordered assembly of these progenitor types and their differentiated derivatives into the developing skeleton. The activation of similar programs underlies effective repair of bone fracture in most instances, though large gaps remain a problem. In contrast, chronic injury at joint surfaces results in arthritis in more than 27 million Americans. Our aim is to identify how transcriptional networks program shared and distinct actions of cartilage and bone forming cells. The research forms a logical base for developing new approaches to skeletal repair and regeneration.
Neural Progenitor Programs in the Nervous System
The development of a functional nervous system requires the formation of a diverse array of neurons. These arise from distinct populations of neural progenitors. When and where progenitors form depends on extracellular signals such as Sonic hedgehog (Shh). Shh acts in a time- and concentration-dependent manner to specify a range of distinct neural progenitor classes in the developing brain and spinal cord. Among these progenitors are those that form the neurons lost in Parkinson’s and Lou Gehrig’s disease. In the adult brain, Shh also controls adult neural stem cells. Shh signaling at the cell surface is transduced into different levels of Gli transcriptional regulators bound to their DNA targets, switching gene activity on or off. We use neuralized embryo stem cells and mouse models to study Gli-targets, and the Gli-directed mechanisms, regulating organization and function of the nervous system.