Alana O'Reilly, PhD
Office Phone: 215-214-1653
Lab Phone: 215-214-3219
Decades of research have demonstrated that a balanced diet is elemental for human health. Malnutrition affects all socioeconomic levels and cultures, with particular impact on individuals in low resource settings. However, our understanding of how individual nutrients effect the cellular changes associated with aberrant states is at its infancy. The underlying hypothesis for our work is that each component of a balanced diet influences signal transduction pathways in target cells, resulting in a collective developmental response within tissues. Our goal is to map the signal transduction pathways targeted by individual nutrients in vivo, in order to build a comprehensive mechanistic understanding of how dietary imbalance affects normal development and identify inexpensive, widely accessible interventions to reduce and treat cancer and other diseases.
Dietary cholesterol controls stem cell proliferation via Hedgehog (Hh) signaling
Our lab recently identified a novel mechanism that translates levels of dietary cholesterol to control proliferation of a single cell population, epithelial Follicle Stem Cells (FSCs), within the Drosophila ovary. Cholesterol levels are sensed by its protein receptor (DHR96) within a subpopulation of ovarian cells that produce the growth factor Hedgehog (Figure 1). In starved flies, Hh is held on the producing cells by the transmembrane protein Boi. Upon feeding, cholesterol binds to its receptor and triggers the activation of a series of proteins to alter the structure of Boi, promoting Hh release and driving stem cell proliferation. Thus, cholesterol consumption regulates the balance between Boi-mediated Hh sequestration and release, allowing for a rapid response to changes in nutrient status and providing a mechanism for controlling egg production rates based on availability of nutrients that assure progeny survival. Current efforts are focused on defining the biochemical changes that mediate Hh release, determining the downstream consequences of Hh release within FSCs, and assessing the contribution of this mechanism to cancer.
Stem Cell Communication within the niche
One striking finding from our work is that FSCs exhibit long, axon-like projections that may mediate communication between stem cells and other cells within the niche. A genetic screen performed in the lab uncovered a number of genes that appear to control FSC projection dynamics and interactions with other cell types. Current work focuses on determining the biological effects of altering gene function on stem cell lifetime and communication between cells within the niche.
Mapping nutrient targets during development
An unusual aspect of the lab is a large number of high school student trainees who participate directly in our research. The research branch of our Immersion Science program for high school students aims to determine the direct molecular targets of dietary nutrients by determining their developmental effects in varied genetic backgrounds in the fly. This work involves hundreds of high school students in the FCCC Teaching Lab here on campus and in high school classrooms in Philadelphia and the surrounding counties, as well as graduate students and postdoctoral fellows who follow-up initial results from the program with advanced approaches. We have found that high school students produce reproducible, high quality data that is in peer-reviewed publications, suggesting that crowdsourcing of cancer-relevant experiments among hundreds of students is a successful and inexpensive approach to large-scale understanding of the roles of specific nutrients in development. Current work focuses on nutrients that target the Ras, Hedgehog, and nuclear hormone receptor signaling pathways.