NSF-BSF: Mechanism of Cuticle Remodeling by Hypoxia

The skin is a line of defense between an animal’s interior and the external world, and the structure and function of the skin affects organismal survival. This research investigates how skin structure and function change in response to low oxygen conditions (hypoxia) and will elucidate the underlying biological mechanisms involved. Plastic responses and adaptation to low oxygen are important for understanding respiration and organ stability and function.

Moreover, since many animals live in habitats where oxygen levels fluctuate (e.g., in water or underground burrows), this research will help understand how animals survive in challenging ecological niches. This study will test the hypothesis that environmental hypoxia impacts skin permeability and will identify specific molecules and regulatory processes involved, in the nematode Caenorhabditis elegans.

Like all animals, C. elegans is covered with skin, and the outermost skin layer is called the cuticle. The cuticle layer is rich with collagen proteins, which are common proteins in the animal kingdom but can be difficult to study because of the many varieties. This project will expand the understanding of collagen and other proteins that regulate collagen structure and function, and the effects on skin structure and function.

The researchers will expand their community outreach activities by developing and disseminating podcasts and educational videos that communicate scientific research results and highlight the contributions of individuals from different backgrounds to scientific studies; communications will be made available in four different languages. This collaboration supported by the NSF-BSF program will provide a fruitful platform for research exchanges between students and postdoctoral fellows in the United States and Israel.

Skin is a multifunctional organ that serves as a barrier and a communication interface between an animal’s interior and the external environment. A central component of the skin is a three-dimensional network of biological molecules, the extracellular matrix, which is composed of proteins, including many forms of collagen. The objective is to understand how hypoxia affects the structure and function of the skin and decipher the cellular and molecular mechanisms underlying these processes, using C. elegans as a model.

Two hypotheses will be tested: (1) the cuticle structure is remodeled and modified in response to hypoxia; (2) Hypoxia Inducible Factor 1 (HIF-1) regulates cuticle structure in a proline-hydroxylation-dependent manner, via post-translational modification. The project will assess the impact hypoxia has on cuticle remodeling using genetic, cellular, and physiological analyses; compare the protein composition of the cuticle in animals exposed to hypoxia or normoxia using targeted proteomics analysis; and determine the mechanism by which HIF-1 controls cuticle remodeling in hypoxia using biochemical, imaging, and genetic approaches.

The proposed research could have a transformative impact on the understanding of the role skin plays in adjusting and adapting to fluctuating environmental oxygen levels.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.