Plasticity and Nitric Oxide Signaling: Identifying the Novel Adaptive Mechanisms Associated with Response to Hypoxia

项目总结 为了维持动态平衡，多细胞真核生物采用了专门的机制来增强氧气 摄取和分配，导致动态的呼吸系统和循环系统，能够对 局部、生物和时间层次上氧气可利用性的变化。低氧生存的关键在于 综合生理反应，如代谢抑制，对氧化损伤的保护和 血流重新分配-一氧化氮和氧化应激途径都是应对 低氧，由于其与血管形成和炎症的关系；从而理解这些因素的作用 玩家将是阐明这种常见和有害的人类疾病的关键，这些疾病依赖于 血管的病理变化(即心血管疾病)。独立之路奖将 使我能够继续一个雄心勃勃的研究计划，研究收敛的适应机制 与氧气限制环境相关，并剖析这些基因调控网络的作用 与缺氧有关，使用斑马鱼。这项提议将检验(目标1)相似基因和 调节网络是适应缺氧环境的基础，即。高空，在 独立的动物谱系，(目标2)对低氧暴露的可塑性反应利用这些基因 与一氧化氮生化途径有关，最后(目标3)早期暴露在低氧环境中可能会 作为成虫进行预驯化，也可以通过改变表观基因组和 转写景观。在期刊上发表了7篇第一作者论文，包括最近在 美国国家科学院院刊(PNAS)，以及分子生物学和进化，我有一个 无可挑剔的研究、生产力和创造力的记录。拟议的实验将为我提供 在生物信息学、基因组学、分子遗传学和使用斑马鱼作为模型方面的宝贵培训。在……下面 在内森·克拉克博士的指导下，我将获得过渡到 独立的学术立场。为了促进我的职业发展，我将在会议上发表演讲，导师 学生，参加相关课程，并发表我的发现。我召集的K99指导委员会， 由Warren Burggren博士、Michael Hiller博士、Joseph Prchal博士和Kristen Kwan博士组成的 在进行比较基因组学时使用大规模基因组数据所需的专业知识，充分利用 斑马鱼作为模型的能力，以表征一氧化氮途径在调节细胞可塑性中的作用 低氧反应，并分析低氧暴露如何影响发育和跨代 可塑性。我将参加正式的培训机会，并寻求参加著名的海洋生物 使用斑马鱼作为模型的强化培训的实验室(MBL-UChicago)技术课程。

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.