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.

项目摘要 为了维持稳态，多细胞真核生物采用了专门的机制来增强O2 吸收和分布，导致动态呼吸系统和循环系统，能够响应 局部，生物和时间水平上的O2可用性变化。缺氧生存的关键在于 合并的生理反应，例如代谢抑郁症，防止氧化损伤和 血流的重新分布 - 一氧化氮和氧化应激途径都是关键参与者 缺氧，由于其与血管形成和炎症的关系；因此了解这些角色 玩家将是阐明依赖于这种常见和有害的人类疾病的关键 血管的病理变化（即心血管疾病）。获得独立奖的途径将 使我能够追求一项雄心勃勃的研究计划，以调查收敛的自适应机制 与氧限制环境相关，并剖析这些基因调节网络的作用 使用斑马鱼与缺氧相关。该提案将检验（目标1）相似基因和 监管网络是适应氧气限制环境的途径，即。高空，IN 独立的动物谱系，（目标2）塑料对低氧暴露的反应利用了基因 与一氧化氧化物生化途径相关，最后（AIM 3）早期暴露于缺氧可以允许 成年后的预言，并通过更改表观基因组和 转录组景观。在期刊上有7份第一份第一名著名出版物，包括最近的出版物 美国国家科学院（PNAS）和分子生物学和进化论文集，我有一个 研究生产力和创造力的无可挑剔的记录。拟议的实验将为我提供 在生物信息学，基因组学，分子遗传学和斑马鱼作为模型的使用方面有价值的培训。在下面 内森·克拉克（Nathan Clark）博士的指导，我将获得过渡到一个经验和培训 独立的学术职位。为了进一步发展我的职业发展，我将参加会议，导师 学生，参加相关课程，并发布我的发现。我组装的K99指导委员会， 由沃伦·伯格伦（Warren Burggren）博士，迈克尔·希勒（Michael Hiller）博士，约瑟夫·普尔查尔（Joseph Prchal）博士和克里斯汀·夸（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的必要专业知识，充分利用 斑马鱼的力量是表征一氧化物途径在介导可塑性中的作用的模型 缺氧反应，并分析低氧暴露如何影响发育和转世 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学 实验室（MBL-uchicago）技术课程，用于使用斑马鱼作为模型进行激进培训。