Research & Initiatives
The research projects in the Bensinger lab are centered on understanding how lipid metabolism influences cellular fate and function. Sometimes our research focuses on normal physiologic conditions, such as the generation and regulation of inflammation and immunity. Other studies investigate how alterations in lipid metabolism contribute to diseases and whether targeting lipid metabolism might be therapeutic. In close collaboration with the UCLA lipidomics laboratory, we develop new approaches to understand better the biochemical pathways and complex features of the mammalian lipidome. Below, we highlight a few exciting ideas and projects the lab is investigating. We hope you enjoy the highlights of our projects.
Major research initiatives:
For over a decade, scientists in the Bensinger lab have investigated how different activation signals reprogram the lipid metabolic state of immune cells and determine why these changes occur. We have shown that immune cells undergo rapid and profound remapping of their lipid composition using advanced mass spectrometry platforms. In some studies, we find that changes in lipid metabolism help to ensure appropriate inflammatory responses and immune cell effector functions. In other instances, we find that specific lipid metabolic features are required to induce anti-inflammatory states and ramp down immunity. Finally, we have been translating information about the changes in lipid metabolism during immune responses to generate new therapeutic approaches for human disease. Please take a look at a few of our exciting projects below.
Targeting lipid metabolism to attenuate tissue destruction in necrotizing soft tissue infections
Necrotizing Fasciitis (NF), or flesh-eating disease, is a medical emergency caused by infection of select gram-positive microbes. These microbes release toxins that induce massive tissue destruction, complicating perfusion to the wound area and decreasing the effectiveness of systemic antibiotics. In the laboratory, we discovered that interferons could quickly alter cell cholesterol synthesis. This abrupt change in cholesterol homeostasis renders cells resistant to pore-forming toxins produced by microbes responsible for Necrotizing Fasciitis. Importantly, this principle seems to apply to the skin, where we can alter tissue sensitivity to toxin damage by genetically altering sterol metabolism. A working model of this process is detailed below. Ongoing studies investigate whether directly targeting cholesterol metabolism in infected tissues can spare them from the massive tissue destruction observed in these deadly infections.
Understanding the molecular circuitry linking interferons with mevalonate metabolism
Viral infections rapidly hijack a cell's metabolic machinery, likely facilitating its lifecycle and evading the host's immune system. One of the metabolic pathways often targeted by foreign invaders is mevalonate metabolism. Although it is not entirely clear why there might be such a concerted effort by viral infections to upregulate flux through the mevalonate pathway, it is generally thought that the products of this metabolic pathway are required for viral replication and pathogen budding. Perhaps not surprisingly, we and others have shown that anti-viral cytokines decrease the metabolic activity of the mevalonate pathway to limit the availability of these essential metabolites. A few years back, we discovered that limiting a cell's ability to flux metabolites through the mevalonate pathway resulted in heightened interferon and more efficient anti-viral responses. These data led us to propose that an IFN-cholesterol circuit exists where IFNs regulate sterol metabolism and sterol metabolism regulates IFN-mediated response. Ongoing work in the lab is deciphering the molecular components of this intriguing circuit and determining why these two seemingly disparate pathways are inextricably linked.
Investigating how and why immune signals reprogram the lipidome of immune cells
Immune activation signals reprogram the lipid metabolic programs of innate and adaptive immune cells. However, a systems-level understanding of how these changes come about and the extent to which different signals reshape the lipidome of an immune cell remains incomplete. In the laboratory, we have dedicated ourselves to using mass spectrometry to create an in-depth picture of how activation programs the lipidome. Our results show that the engagement of pattern recognition receptors (PRR) that sense components of microbial and viral invaders drive the remapping of macrophage lipid composition. Unexpectedly, we observed that PRR-induced changes in lipid composition occur in a signal-specific manner. We find that activating anti-viral pathways drives cells to acquire a distinct lipidome. In contrast, activating anti-microbial responses causes cells to develop a different lipidome. The signal-specific nature of lipid metabolic reprogramming leads to the hypothesis that reshaping the lipidome is necessary to support effector functions and ensure proper regulation of inflammation. In proof-of-concept studies, we found that inhibiting flux through the desaturase SCD prolonged inflammation and enhanced clearance of microbial infections. Ongoing studies in the lab further explore how manipulation of lipid composition influences inflammation and host defense responses.
Discovering the lipid metabolic programs of cancer
It is now well understood that cancer cells have altered lipid metabolic programs to facilitate growth, survival, and metastasis. In the laboratory, we have been applying our knowledge of lipid biology to define the lipidome of glioblastoma, a uniformly lethal brain cancer. We are also asking if targeting specific lipid metabolic pathways can be used as an adjunctive therapeutic approach for this deadly disease. Applying a combination of shotgun lipidomics and stable isotope tracers, we have identified specific metabolic pathways preferentially relied upon by this aggressive brain cancer. Genetically or pharmacologically targeting these pathways reduce cell growth and viability in a dish. More importantly, preliminary results show that treating mice with experimental drugs that can cross into the brain leads to a growth-inhibitory effect of human glioblastoma. Although it is early days, we are excited about these new studies. Stay tuned for more exciting results coming through the lab pipeline.
Development and application of advanced analytical techniques to assess lipid homeostasis
The mammalian lipidome is exceedingly complex, and it is estimated that a given cell has well over 1000 different lipids contributing to cellular lipid composition. An additional layer of complexity is that cells have the capacity to synthesize or import key lipid building blocks. In close collaboration with Dr. Kevin Williams and his team at the UCLA Lipidomics Lab, we have been developing new methods and techniques for interrogating this complex biology. We have developed new approaches to isolating lipids from cells or tissues, developed better modeling programs to understand how cells acquire lipids, and created new software for assessing the lipidome. Current work in the lab is focused on developing new methods for assessing the origin of lipids used in building the lipidome of different tissues or cancers in mice. We are also working with our many expert collaborators at UCLA to understand how a cell's lipidome might influence other fundamental aspects of cell biology, such as gene expression and signaling. We hypothesize that lipid composition is sensed by the cell and that this information is sent to the nucleus to shape development, differentiation, and functional programs. Although these concepts are complex, and our understanding is rudimentary, we are excited to jump into the deep end of the "scientific pool" to answer this difficult question.
