Response of aged thymus to injury and rejuvenation signals

PROJECT 1- Abstract Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. However, this capacity declines with age and is a major clinical hurdle in elderly patients who receive an immune insult such as that caused by common cancer cytoreductive therapies and the conditioning required for hematopoietic stem cell transplantation (HCT). The premise of this project is that the thymic regenerative response to acute injury is weakened with age and correlates with age-related thymic involution. We will compare and contrast what we know about the cellular and molecular pathways that underpin thymic regeneration in young animals, to the regenerative response in mice during normal thymic aging; and develop rational intervention strategies to improve regeneration in aged mice. In this project, we will comprehensively assess the endogenous regenerative response over lifespan, with particular emphasis on sex differences with age (SA1); perform studies to better understand the underlying mechanisms governing endogenous thymic regeneration and their breakdown in aged mice, focusing on the balance between inflammatory and pro-regenerative signals from dying cells after acute damage (SA2); and develop therapeutic strategies based on these test known and putative strategies to determine their effectiveness in promoting thymopoiesis in aged tissue at baseline or that has undergone damage (SA3). Our project has multiple points of interaction with the other projects and cores of this P01, including a focus on the hematopoietic and non-hematopoietic stromal microenvironment, regulation of Notch-DLL4 interactions, and of utmost importance, a comprehensive shared sequencing dataset that can be leveraged across the program. Together, these aims and interactions support the overarching goal of the P01 to identify the mechanisms responsible for defects in thymic production of naïve T cells with age and develop methods to improve or reverse them. Therefore, the mechanistic and pre-clinical studies outlined have the potential to define important novel pathways underlying thymic regeneration, which could result in clinical approaches to enhance T cell immunity in patients whose thymus has been decimated due to age-related involution.