Understanding age-related immune dysfunction using human model systems (360G-Wellcome-323265_Z_24_Z)

The bone marrow sustains lifelong blood and immune cell production. As we age, disruptions to the specialized niches that support healthy haematopoiesis drive immunosenescence and inflammation—major risk factors for cardiovascular disease, cancer, and severe infection. While cell-intrinsic causes of haematopoietic aging are well studied, the role of altered cellular crosstalk in aged micro-environments remains poorly understood. Fundamentally, this is due to the limitations of mouse models in the context of human bone marrow niches, as well as the lack of physiologically relevant human models. This research will (1) investigate how age-related changes in stromal cell differentiation alter myeloid and lymphoid output using a human organoid model of the aged bone marrow niche, (2) examine how vascular aging contributes to haematopoietic dysfunction in a micro-fluidic platform, and (3) define the impact of altered haematopoiesis on thymic remodelling in a co-culture model of thymus and bone marrow organoids. I will build on my skills as a bioengineer and bring together fundamental scientists and clinicians to provide insights into aging niches and their effects on haematopoiesis. My aim is to generate much needed human models of complex tissues to advance basic and translational research, and inform strategies for mitigating immune decline.