The human body is estimated to remove 1 percent of its body mass, likely more than 200 billion cells, every day. To achieve this, we rely on a highly evolutionarily conserved process: apoptotic cell clearance or efferocytosis. The long-term goal of our lab is to understand how phagocytes handle the immense burden of ingestion and digestion of apoptotic corpses — a process essential for normal development and tissue homeostasis, but also cancer development and progression. We hope to use the information gained through basic studies of efferocytosis to design novel therapeutics.
The human body is estimated to remove more than 200 billion dead cells every day. This clearance of apoptotic cells, or efferocytosis, is carried out by phagocytes such as macrophages, which are fewer in number. Efferocytosis is essential for normal development and tissue homeostasis, but also pathogen defense and anti-tumor immunity. A single phagocyte typically ingests an entire apoptotic corpse, essentially doubling its content. Because phagocytes often ingest multiple targets in succession, we propose the existence of “rapid-response circuits” composed of kinases that sense and activate in response to the change in a given solute, and solute transporters downstream of these kinases that impart the necessary flux of solutes. We believe these circuits allow phagocytes to handle the risk that corpse content poses to the homeostasis of both the phagocyte and ultimately the host. The central focus of our research program is to understand these rapid-response circuits governing how a phagocyte manages such excess cargo influx, how this relates to host immune function and homeostasis, and how these processes are exploited in cancer development and progression.
The Perry lab combines cell biological, immunological, and informatics approaches to investigate the following:
- Elucidate rapid-response circuits required for phagocytes to maintain internal homeostasis. We focus on circuits involving solute-sensing kinases and the solute carrier (SLC) transporters they regulate. We are especially interested in SLCs because they are understudied transport proteins required for diverse physiological functions, are causally linked to more than 100 human diseases, and are readily druggable.
- Metabolic adaptation by phagocytes during uptake and digestion of apoptotic corpses. Efferocytosis involves a series of distinct steps, each posing unique metabolic challenges. We study how phagocytes utilize rapid-response circuits to sense and respond to this changing metabolic burden.
- Determine the importance of rapid-response circuits to homeostatic efferocytosis and tumor development/progression. My lab seeks to link our mechanistic work on rapid-response circuits to in vivo studies of tissue-resident and tumor-associated phagocyte function in relevant preclinical mouse and zebrafish cancer and autoimmunity models. The hope is that such studies will inform the design of novel immunotherapeutics.