This is a predoctoral fellowship application to support an MD/PhD trainee at the University of Pennsylvania Perelman School of Medicine in her goal to become a physician-scientist. The proposed research aims to dissect the role of the class I histone deacetylase HDAC3 in keratinocyte-mediated innate immunity. Currently, class I HDAC inhibitors are used for the treatment of cutaneous malignancies. These drugs inhibit class I HDACs nonspecifically. The mechanisms of action of HDAC inhibitors remain unclear, and they have undesirable side effects. Elucidating the roles of specific class I HDACs in the epidermis will improve current understanding of skin biology and inform the development of improved treatment options for skin disease. The proposed studies will utilize a mouse model in which Hdac3 deletion can be induced specifically in the skin.
Aim 1 will address the hypothesis that HDAC3 modulates the keratinocyte response to skin commensal bacteria. This will be achieved through in vitro keratinocyte stimulations, antibiotic treatment of mutant and control animals, and rederivation of mutant and control animals in germ-free conditions.
Aim 2 will address the potential mechanisms through which HDAC3 represses innate immune signaling using a series of in vitro ChIP, co-IP and small molecule inhibitor studies. Anticipated results have the potential to inform the development of improved therapeutics for the treatment of skin cancer and skin inflammatory diseases such as psoriasis.
The mechanisms underlying the appropriate development of the skin barrier remain incompletely understood, particularly with respect to the role of chromatin regulation in this context. Inhibition of histone deacetylases (HDACs), a type of epigenetic enzyme, is a promising means for treating hyperproliferative skin conditions; however, HDAC inhibitors act non-specifically on multiple HDACs and have severe side effects. This proposal will delineate the role of the histone deacetylase HDAC3 in the skin, which will improve current understanding of skin biology and disease, and has the potential to inform the design of improved therapeutics for skin cancer and skin inflammatory diseases.
