Studying tissue size regulation, leading to potential therapeutics for tuberculosis
Our laboratory is currently working on three areas of biomedicine, trying to move observations from basic research into the clinic. First, we are studying how the sizes of tissues and tumors are regulated, and how this can be manipulated for therapeutic purposes. As a model system, we are using the simple eukaryote Dictyostelium discoideum, which allows us to combine techniques such as biochemistry, genetics, computer modeling, and cell biology to study tissue size regulation. We have found that the unusual molecule polyphosphate acts as a secreted signal in that allows Dictyostelium cells to sense their local cell density. In a negative feedback loop, at high cell densities, the concomitant high extracellular concentrations of polyphosphate cause Dictyostelium cells to inhibit their proliferation, and we are studying the signal transduction pathway to understand similar mechanisms in humans.
Like macrophages, Dictyostelium cells phagocytose and kill bacteria. We noticed that lower concentrations of extracellular polyphosphate cause some Dictyostelium cells to ingest but not kill bacteria, possibly to carry a food supply, much like the farming observed by Debby Brock and Joan Strassman. Mycobacterium tuberculosis (M. tb), the causative bacteria for tuberculosis, is ingested but not killed by macrophages. We found that M. tb also secretes polyphosphate, and that this appears to at least in part cause macrophages to not kill them. Using both Dictyostelium and human macrophages, we are studying how the M. tb polyphosphate signal is sensed by cells, and identifying ways to block this sensing pathway so that macrophages will ignore the polyphosphate ‘don’t kill me’ signal, and kill ingested M. tb. We found that a drug which blocks a polyphosphate signal transduction pathway found in Dictyostelium causes human macrophages to increase their killing of ingested M. tb. Current lab efforts for this project are on expanding understanding of the polyphosphate ‘don’t kill me’ signal transduction pathway to develop more potential therapeutics for tuberculosis. Please click here for more information.
Studying chemorepulsion, leading to potential therapeutics for ARDS
Second, we are studying how some secreted proteins can make cells move away from the source of the signal. We found such a signal (called a chemorepellent) in Dictyostelium, and then found a similar signal in humans. The human signal repels neutrophils, and we found that this can be used therapeutically in mouse models of neutrophil-driven diseases such as rheumatoid arthritis and acute respiratory distress syndrome (ARDS). We found that the Dictyostelium and human neutrophil chemorepulsion signal transduction pathways have remarkable similarities. Surprisingly, neutrophils from men and women have a variety of subtle but significant differences in their chemorepulsion mechanisms. Current lab efforts for this project are on further understanding how eukaryotic chemorepulsion works, trying to understand why men and women have differences in neutrophils (a fundamental aspect of the innate immune system), and moving potential therapeutics for ARDS and other neutrophil driven diseases into the clinic. Please click here for more information.
Developing therapeutics for fibrosing diseases
Third, we have found that a human blood protein called Serum Amyloid P (SAP) regulates a key step in the formation of scar tissue as well as the formation of the scar-like lesions in fibrosing diseases such as congestive heart failure and pulmonary fibrosis. We are studying this mechanism, and a biotech company (Promedior) we co-founded showed that SAP has an excellent ability to inhibit (and in some patients possibly reverse) fibrosis in patients in two Phase 2 trials. Roche bought Promedior and is now doing Phase 3 trials of SAP in patients with pulmonary fibrosis. Current lab efforts for this project are on elucidating basic mechanisms driving fibrosis, and on developing next-generation potential therapeutics for fibrosing diseases. Please click here for more information.