In order to maintain its protective function, the epidermis undergoes a continual process of homeostatic renewal in which cells within the proliferative basal layer withdraw from the cell cycle and differentiate as they process through the suprabasal epidermal layers. The morphological and genetic changes associated with epidermal keratinocyte differentiation are well described. How other molecular mechanisms, such as metabolic reprogramming regulate epidermal homeostasis, have not been extensively studied. We recently demonstrated that oxidative mitochondrial metabolism and reactive oxygen species (ROS) production are critical regulators which promote keratinocyte differentiation. Mice which lacked mitochondrial metabolism and ROS generation in basal epidermal cells exhibited impaired epidermal differentiation and increased levels of proliferative basal cells. We further demonstrated that ROS produced at mitochondria act as critical signaling molecules which promote the propagation of Notch signaling events which are required for keratinocyte differentiation. In the current proposal, we will build on our recently-reported findings to dramatically extend our understanding of how the epidermal differentiation program regulates cellular metabolism to promote differentiation or to maintain basal cells in the undifferentiated state. We will focus our attention on p63, a transcription factor required for epidermal development and homeostasis. p63 belongs to a family of transcription factors which are known to be regulators of cellular metabolism and ROS levels. We will use gain and loss of function studies to determine how p63 expression affects keratinocyte glycolytic and oxidative metabolism. We will closely examine how p63 expression affects metabolite flux through biosynthetic pathways and how p63 expression affects levels of cellular ROS. We will also explore the known repressive effect that p63 has on Notch. We will determine if p63 regulates Notch through repression of ROS-mediated signaling. Our studies will determine how keratinocyte metabolism changes during differentiation and will determine the causal role that metabolic reprogramming plays in promoting differentiation. The work proposed herein will provide the applicant with the training required for development into an independent skin biologist. This proposal builds off of the existing strengths of the applicant and adds to his abilities with additional training in epidermal and epithelial biology. The collaborative environment present at Northwestern University will ensure that the work is completed expeditiously and efficiently. Importantly, the training provided for in this proposal will allow applicant time to take advantage of opportunities for career development available at Northwestern University. These include workshops in grant writing, mentoring, teaching, and responsible conduct of research.

Public Health Relevance

There are over 100 skin diseases which effect over 20% of the population. In many cases, the genetic cause of disease is unknown and thus, there is a need for a greater understanding of the molecular mechanisms by which epidermal homeostasis is achieved. Discovery of metabolic mechanisms which promote epidermal homeostasis may provide novel therapeutic targets for treatment of disease as well as provide new strategies that will promote wound healing and aid in skin regenerative medicine.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Baker, Carl
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Hamanaka, Robert B; Nigdelioglu, Recep; Meliton, Angelo Y et al. (2018) Inhibition of Phosphoglycerate Dehydrogenase Attenuates Bleomycin-induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol 58:585-593
Wu, David; Huang, Ru-Ting; Hamanaka, Robert B et al. (2017) HIF-1? is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. Elife 6:
Hamanaka, Robert B; Mutlu, Gökhan M (2017) PFKFB3, a Direct Target of p63, Is Required for Proliferation and Inhibits Differentiation in Epidermal Keratinocytes. J Invest Dermatol 137:1267-1276
Huang, Ru-Ting; Wu, David; Meliton, Angelo et al. (2017) Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling. Am J Respir Crit Care Med 195:639-651
Nigdelioglu, Recep; Hamanaka, Robert B; Meliton, Angelo Y et al. (2016) Transforming Growth Factor (TGF)-? Promotes de Novo Serine Synthesis for Collagen Production. J Biol Chem 291:27239-27251
Hamanaka, Robert B; Weinberg, Samuel E; Reczek, Colleen R et al. (2016) The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia. Cell Rep 15:451-459
La, Jennifer; Reed, Eleanor B; Koltsova, Svetlana et al. (2016) Regulation of myofibroblast differentiation by cardiac glycosides. Am J Physiol Lung Cell Mol Physiol 310:L815-23