Regulation of zinc-dependent lysosome morphological restructuring, zinc trafficking and low zinc homeostasis in C. elegans and human model systems

Project Summary/Abstract Dysregulation of zinc homeostasis can lead to either zinc deficiency or zinc excess, resulting in a variety of human pathologies. Therefore, strict regulation of zinc trafficking and storage are essential for cellular function and human health. Robust studies of zinc biology can be conducted with a variety of model systems, and I propose to combine the genetic and experimental power of Caenorhabditis elegans with the medical relevance of human cell culture to develop a detailed and useful understanding of zinc biology. Studies from my early postdoctoral training have uncovered that lysosome-related organelles, called gut granules in C. elegans, are restructured in a zinc dependent manner; I identified an expansion compartment that increases in volume in zinc excess and deficient conditions. In addition, the low zinc homeostasis pathway appears to be conserved in C. elegans and humans, since the Low Zinc Activation enhancer element has been identified in the promoters of zinc transporters that function the low zinc response in both organisms. To build upon these preliminary results, I propose to take a multidisciplinary approach to understand how low zinc homeostasis is regulated and how lysosomes are restructured. In Aim 1, I propose to characterize the zinc-dependent expansion compartment and the membrane architecture of intestinal gut granules in C. elegans. In Aim 2, I will elucidate the regulation of zinc trafficking and morphological restructuring of human lysosomes. In Aim 3, I will characterize the regulation of the low zinc pathway in C. elegans and human cells. This proposal will capitalize on my experience with interdisciplinary techniques from cell biology, chemistry, and X-Ray physics, and expand upon them to complete my toolkit for probing zinc in biology with genetics and biochemistry. Furthermore, I will expand into human cells as a model system. The training will also build upon my extensive experience in science advocacy and equip me to be a powerful advocate for historically marginalized groups as a faculty member. My training in the K99 phase will integrate the expertise from my mentor Dr. Kornfeld and co-mentor Dr. Diwan to complete my preparation for the R00 independent phase. Training during the K99 phase will integrate the experience from my mentors, collaborators, and advisory board members to springboard my career as a scientist and science activist. My long-term career goal is to lead a team of diverse trainees performing cutting edge techniques to probe critical questions in zinc homeostasis and trafficking. I have a strong record demonstrating my abilities as a scientist, and therefore my potential as a primary investigator. I am committed to conducting leading edge science AND promoting institutional change to promote diversity and inclusion in academia. The K99/R00 award will maximize my chances of being able to achieve my goals by providing critical resources and connections that would be otherwise be lacking in my training.