Grant: Discovery Grants Program - Individual

The overall long-term objective of my research program is to understand the mechanisms that govern the regulation of pro- and anti-inflammatory states in liver macrophages. The liver is a vital organ that must be protected from the foreign nature of entities associated with our diet, the damaging effects of pathogenic insult and environmental toxins and other tissue-damaging inflammatory challenges. In health, the liver operates in a state of immunological tolerance, largely mediated by immune cells known as macrophages. Inherent mechanisms of liver resident macrophages called Kupffer cells (KC) firmly tread a delicate balance between a state of tolerance (anti-inflammatory) while bearing potential for activation towards pro-inflammatory functions. In studying human blood-derived macrophages, we have found that regulating the production of a pro-inflammatory secreted protein called interferon (IFN)-gamma  by macrophages is central to this balance. We have identified candidate signaling pathways that may underlie this secretion, some of which suggest an intersection with the metabolic processes of macrophages. We aim to translate these findings to the human liver while taking advantage of experimental tools and animal models, determining parallels in KCs. In addition, we will directly interrogate the impact that bacterial endotoxin (lipopolysaccharide, LPS) and prevalent environmental toxins known as polyfluoroalkyl substances (PFAS) on macrophage subset polarization in the liver. Mechanistic studies include an assessment of underlying DNA remodeling that lend KCs and macrophages the propensity to resist activation towards inflammation. We also will investigate the novel influence of liver-derived mesenchymal stem cells (MSCs) in mediating macrophage polarity in health. Studies of liver macrophages polarity are logistically challenging, particularly in humans, and require careful and intentional translation of knowledge gained in blood monocyte-derived macrophages. This research program navigates these lines in planning its research questions and approaches, using human specimens and relevant animal models. We propose that an integrated research approach, involving broad interrogation of circulating monocyte-macrophages, in humans and animal models, will inform focused investigations on liver macrophages and KCs to address identified gaps in knowledge. This research program is designed in consideration of potential sex effects on immune cell function, particularly as women have decidedly different rates of liver disease progression that are likely rooted in inherent threshold differences in immune cell activity in health. In addition, the laboratory is comprised of a racially diverse and equitably balanced team of highly qualified personnel, spanning a spectrum of educational training programs and technical staff.