PROJECT SUMMARY / ABSTRACT: The skin functions as a potent immune organ, rendering the readily accessible cutaneous microenvironment an attractive target that can be locally engineered to induce and regulate systemic immune responses. Increasing age is associated with changes in immune function (immunosenescence) that result in increased susceptibility to diseases and poor vaccine responses in older adults. This proposal is designed to bring together very recent and significant advances in dermatology and skin biology to address critical problems in human health. Here, we specifically focus on the skin microenvironment and strategies for cutaneous immunomodulation. The overall approach is to utilize a clinically applicable dissolvable microneedle array delivery platform we have developed to locally engineer the highly adaptive and immunoresponsive skin microenvironment. Specifically, we propose to modulate local immune regulatory circuits in the skin to enable the induction and regulation of systemic immune responses. The studies we propose will investigate the effect of locally delivered immune modulators on the mechanisms underlying cutaneous immune regulation in young and aged skin. Importantly, our studies include translational studies using living human skin to enable the rapid advancement of novel cutaneous immunomodulation strategies into clinical trials. The proposed studies will result in a better understanding of skin immunobiology specifically relevant to the development of safe and predictable skin immunoengineering strategies to regulate systemic immune responses across the lifespan.