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

可塑性和一氧化氮信号传导：识别与缺氧反应相关的新型适应性机制

• 批准号: 10351389
• 负责人: Allie M Graham
• 金额: $ 10万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351389
• 关键词: Acclimatization; Adopted; Adult; Affect; Altitude; Animals; Award; Binding; Biochemical; Biochemical Pathway; Bioinformatics; Biological; Biological Assay; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Computing Methodologies; Creativeness; DNA Methylation; Development; Diving; Energy Metabolism; Environment; Epigenetic Process; Eukaryota; Evolution; Exposure to; Future; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Hematopoiesis; Hemoglobin; Homeostasis; Hypoxia; Individual; Inflammation; Journals; Laboratories; Left; Life; Location; Long-Term Effects; Mammals; Mediating; Mentorship; Mitochondria; Modeling; Molecular Biology; Molecular Evolution; Molecular Genetics; Nitric Oxide; Nitric Oxide Pathway; Oxidative Stress Pathway; Oxygen; Pathologic; Pathway interactions; Pattern; Phylogenetic Analysis; Physiological; Polycythemia; Population; Positioning Attribute; Production; Productivity; Proteins; Publications; Publishing; Pulmonary Hypertension; Recording of previous events; Regulatory Pathway; Research; Research Personnel; Respiratory System; Role; Route; Signal Transduction; System; Testing; Training; United States National Academy of Sciences; Vascularization; Work; Zebrafish; angiogenesis; career development; comparative; comparative genomics; developmental plasticity; epigenomics; experience; experimental study; functional outcomes; gene function; gene regulatory network; genome wide association study; genomic data; human disease; improved; member; metabolic depression; novel; offspring; oxidative damage; programs; response; student mentoring; symposium; tenure track; training opportunity; transcription factor; transcriptome sequencing; transcriptomics; uptake

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.

项目概要 为了维持体内平衡，多细胞真核生物采用了专门的机制来增强 O2 吸收和分布，产生动态的呼吸和循环系统，能够响应 局部、组织和时间水平上氧气可用性的变化。缺氧生存的关键在于 综合生理反应，例如代谢抑制、防止氧化损伤和 血流的重新分配——一氧化氮和氧化应激途径都是响应的关键参与者 缺氧，由于其与血管化和炎症的关系；从而了解这些的作用 参与者将成为阐明此类常见且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 使我能够开展一项雄心勃勃的研究计划，调查收敛适应机制 与缺氧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。该提案将检验以下假设：（目标 1）相似的基因和 调节网络是适应缺氧环境的途径的基础，即。高海拔，在 独立的动物谱系，（目标 2）对缺氧暴露的可塑性反应利用基因 与一氧化氮生化途径相关，最后（目标 3）早期暴露于缺氧可能会导致 作为成虫进行预驯化，也可以通过表观基因组和基因组的变化传递给后代 转录组景观。在期刊上发表了 7 篇第一作者论文，其中包括最近在 美国国家科学院院刊 (PNAS) 和分子生物学与进化，我有一篇 研究生产力和创造力无可挑剔的记录。拟议的实验将为我提供 生物信息学、基因组学、分子遗传学和使用斑马鱼作为模型的宝贵培训。在下面 在 Nathan Clark 博士的指导下，我将获得过渡到 独立的学术地位。为了进一步发展我的职业发展，我将出席会议、导师 学生，参加相关课程，并发表我的发现。我组建的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 使用大规模基因组数据进行比较基因组学所需的专业知识，充分利用 斑马鱼作为模型来表征一氧化氮途径在介导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课程 实验室（MBL-芝加哥大学）技术课程，用于使用斑马鱼作为模型的强化培训。