The innate immune system is the group of cells and their products that protect humans and other organisms against invading pathogens. When innate immune cells function abnormally, they can contribute to autoimmune diseases and cancer by secreting incorrect signals to neighboring cells. However, if drugs could specifically target the innate immune cells to return them to a healthy state, then it may be possible to harness them to treat these diseases. The innate immune response - like many other biological systems - is complicated by the fact that not all cells respond exactly the same way to the same stimulus, even though the cells are genetically identical. The goal of this CAREER award is to better understand the innate immune system by measuring noisy signals and secretion in single cells to discover how they work together to produce a protective immune response. This research will use novel experimental tools such as microfluidic devices, that permit measurement of many biological signals from single cells. Computational modeling will be used to interpret these complex single-cell data sets and develop new hypotheses about innate immune system regulation and new ways to modify the innate immune system to treat disease.
An effective immune response requires extensive communication between cells of the innate and adaptive immune systems. Macrophages play a major role in regulating the immune response by executing a well-orchestrated cascade of secreted pro- and anti-inflammatory cytokines upon stimulation by microbial products, such as lipopolysaccharide (LPS). Recently, it has been discovered that there is significant cell-to-cell heterogeneity in innate immune intracellular signaling and secretion responses. The goal of this CAREER award is to test the hypotheses that 1) signaling dynamics regulate secretion heterogeneity; and 2) intercellular heterogeneity is converted to rapid and reliable responses in the population via paracrine (i.e., cell-to-neighbor cell) signaling. To explore these hypotheses, the researchers will use state-of-the-art experimental tools for single-cell analysis, including an integrated microfluidic device for live-cell imaging of signaling, transcriptional dynamics and secretion in the same single cells. These data will be used to classify heterogeneous 'secretion programs' (Specific Objective 1), identify sources of heterogeneity from transcription to secretion across differentially trafficked cytokines (Specific Objective 2), and to develop a mathematical model of signaling, cytokine secretion, and diffusion fit to single-cell data to make predictions about emergent population behavior (Specific Objective 3). The results will have significant implications for immunology, cancer, and beyond, and may suggest improved strategies for specifically modulating the innate immune response to treat disease. Microfluidic tools like the ones used in this research not only enable discovery of new biological mechanisms, but also provide fun and tangible ways to learn foundational skills in biology and engineering. Therefore, this CAREER award will support an educational initiative to increase diversity and participation in engineering through a summer outreach program for high school students in the greater New Haven area. Specifically, the researchers will use microfluidic devices to engage high school students and teach them basic concepts in immunology, biology and engineering through development of a summer teaching module (run through Yale's Pathways to Science Program) and summer lab internships. Such hands-on approaches are critical to recruit and retain a more diverse group of science, technology, engineering and mathematics (STEM) college graduates.
