Project summary
To maintain homeostasis, multicellular eukaryotes have adopted specialized mechanisms to enhance O2
uptake and distribution, resulting in dynamic respiratory and circulatory systems, capable of responding to
changes in O2 availability on local, organismal, and temporal levels. The key to hypoxia survival resides in
combined physiological responses, such as metabolic depression, protection against oxidative damage and
redistribution of blood flow - both nitric oxide and oxidative stress pathways are key players in response to
hypoxia, due to its relationship to vascularization and inflammation; thus understanding the role of these
players would be key in illuminating such common and detrimental human diseases that are dependent on
pathological changes in blood vessels (ie. cardiovascular diseases). The Pathway to Independence Award will
enable me to pursue an ambitious research program investigating the convergent adaptive mechanisms
associated with oxygen-limited environments and dissecting out the role of those gene-regulatory networks
associated with hypoxia, using zebrafish. This proposal will test the hypothesis that (Aim 1) similar genes and
regulatory networks underlie the routes for adaptation to oxygen-limited environments, ie. high-altitude, in
independent animal lineages, (Aim 2) the plastic response to hypoxia exposure makes use of the genes
associated with the nitric-oxide biochemical pathway, and finally (Aim 3) early exposure to hypoxia could allow
for preacclimation as an adult and also be passed onto progeny via changes to both the epigenomic and
transcriptomic landscape. With 7 first-author publications in journals including recent publications in the
Proceedings of National Academy of Sciences (PNAS), and Molecular Biology and Evolution, I have an
impeccable track record of research productivity and creativity. The proposed experiments will provide me with
valuable training in bioinformatics, genomics, molecular genetics and the use of zebrafish as a model. Under
the mentorship of Dr. Nathan Clark, I will gain the experience and training necessary to transition to an
independent academic position. To further my career development, I will present at conferences, mentor
students, attend relevant courses, and publish my findings. My assembled K99 mentorship committee,
composed of Dr. Warren Burggren, Dr. Michael Hiller, Dr. Joseph Prchal and Dr. Kristen Kwan, will provide me
the necessary expertise to use large-scale genomic data in performing comparative genomics, fully utilizing the
power of zebrafish as a model to characterize the role of the nitric-oxide pathway in mediating the plasticity of
hypoxia response, and analyzing how hypoxia exposure affects developmental and transgenerational
plasticity. I will participate in formal training opportunities and seek attendance at renowned Marine Biological
Laboratory (MBL-UChicago) technical courses for intense training in using zebrafish as a model.