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

项目摘要 为了维持体内平衡，多细胞真核生物采用了专门的机制来提高O2 吸收和分布，导致动态的呼吸和循环系统，能够响应 局部、生物体和时间水平上的O2可用性变化。缺氧生存的关键在于 组合的生理反应，如代谢抑制，保护免受氧化损伤， 血流量的重新分布-一氧化氮和氧化应激途径都是响应 缺氧，由于其与血管形成和炎症的关系;从而了解这些的作用， 玩家将在阐明此类依赖于病毒的常见且有害的人类疾病方面发挥关键作用 血管的病理变化（即，心血管疾病）。独立之路奖将 使我能够从事一项雄心勃勃的研究计划，调查聚合适应机制， 与氧气有限的环境相关，并剖析出这些基因调控网络的作用， 与缺氧相关的研究。这项提议将检验假设，即（目标1）相似的基因和 监管网络是适应氧气有限环境的途径的基础，即。高海拔地区， 独立的动物谱系，（目的2）对缺氧暴露的塑性反应利用基因 与一氧化氮生化途径相关，最后（目的3）早期暴露于缺氧可能会使 作为成年人进行预适应，也可以通过表观基因组和 转录组学景观。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）和分子生物学与进化，我有一个 研究生产力和创造力的无可挑剔的跟踪记录。这些实验将为我提供 在生物信息学、基因组学、分子遗传学和以斑马鱼为模型方面的宝贵培训。下 在内森·克拉克博士的指导下，我将获得必要的经验和培训，以过渡到一个 独立的学术地位。为了促进我的职业发展，我将出席会议，指导 学生，参加相关课程，并发表我的研究结果。我召集的K99导师委员会 由Warren Burggren博士，Michael Hiller博士，Joseph Prchal博士和Kristen Kwan博士组成，将为我提供 充分利用大规模基因组数据进行比较基因组学所需的专业知识 斑马鱼作为一种模型来表征一氧化氮途径在介导的可塑性中的作用的能力 缺氧反应，并分析缺氧暴露如何影响发育和代际 可塑性我将参加正式的培训机会，并寻求出席著名的海洋生物 实验室（MBL-UChicago）技术课程，用于使用斑马鱼作为模型的强化培训。

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.