The 2 young researchers who have been recruited in 2025 will present their research projects:

Marion REGNIER: Sex differences in liver insulin signaling: physiological insights and implications for MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, affecting 30% of the adult population. It involves a gradual transition from simple steatosis to steatohepatitis (MASH), often accompanied by fibrosis and long-term clinical outcomes. Biological sex influences the pathogenesis of MASLD, with higher incidence in men compared to premenopausal women. A key challenge is now to identify mechanisms driving early stages of the disease and governing sex-specific features. Insulin resistance is a key modulator of hepatic lipid accumulation and MASLD pathogenesis. However, the relative contributions of hepatic versus peripheral insulin resistance to liver lipid accumulation remain unclear, a complexity further heightened by sex-related differences. With this project, I will take initial steps toward understanding to what extent sex affects the relationship between hepatic insulin signaling and liver lipid accumulation, in health and disease. My objectives are 1) to characterize sex differences in insulin signaling and hepatic lipid metabolism in physiological context, 2) to define sex-specific consequences of defective insulin signaling in hepatocytes and 3) to determine how hepatic insulin resistance promotes the progression from steatosis to MASH and fibrosis.

Matthieu ROUSSEAU: The impact of sex on mucosal tissue resident memory T cell development and function

Women and men are differently susceptible to many diseases and, in turn, respond differently in these disease states. Sex differences in cellular function, or physiological, and pathophysiological processes are major drivers of these divergent responses. Remarkably, sex as a biological variable in research has been historically overlooked, leading to an incomplete knowledge of fundamental processes, such as the development of durable immune memory following bacterial infection. Development of immune memory, including at mucosal surfaces that are particularly at risk for infection, protects a host from the same infection more than once. However, memory often fails at these sites, for reasons that are incompletely understood, leading to recurrence, such as in urinary tract infection (UTI). To understand how mucosal immune memory develops and can be immunomodulated in females and males, my model system is UTI. The bladder is highly vulnerable to UTI, a multidrug resistant infection with one of the strongest sex biases (~50% women vs 5% men). Recently, I described a previously unknown T cell population (TRM) that takes up residence in the bladder after a first infection. These TRM are necessary and sufficient to protect female mice against a second UTI, providing a viable target to boost immunity to UTI. Alarmingly, antibiotic treatment inhibits the development of TRM cells, ablates immune memory in female mice. Remarkably, I found that although the innate immune response to UTI in male mice is significantly diminished compared to female mice, males also develop TRM and immune memory, and quite surprisingly, can do so in the presence of antibiotics. Adding complexity, elimination of bladder macrophages, potential regulators of TRM, improves immunity, however, only in female mice. Thus, I hypothesize that biological sex and sex-specific pathways differently impact the development, regulation, and mechanism of action of this resident memory T cell during UTI. Vaccine and/or immunotherapeutic approaches that can overcome or target sex-specific pathways in bladder TRM biology will lead to treatments for UTI that do not require antibiotics. My objectives to test this hypothesis are to (1) dissect TRM development in the bladder during UTI, (2) decipher how TRM mediate protection and are regulated during recurrence, and (3) evaluate immunotherapeutic approaches to improve immunity to recurrent UTI in both sexes.