Collaborative Research: URoL:Epigenetics 2: Epigenetic pathways to regulate homeostatic resilience: Model-based discovery of rules across diverse mammals

合作研究：URoL：表观遗传学 2：调节稳态恢复力的表观遗传途径：基于模型的不同哺乳动物规则发现

基本信息

批准号：
2022046
负责人：
Allyson Hindle
金额：
$ 88.41万
依托单位：
University of Nevada Las Vegas
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2022046&HistoricalAwards=false
关键词：
Collaborative Research URoL Epigenetics Epigenetic

项目摘要

This project will examine biological rules that govern how different species respond, at the cellular level, to changes in their environment, and why some species are more robust than others. All species encounter environmental variation, but some tolerate extremes that would be dangerous to most other species. Fruit bats withstand dramatic changes in blood glucose between feeding and flying, camels tolerate high body temperatures in hot desert environments, and deep-diving mammals survive with little oxygen during long dives. The goal of this project is to understand how diverse species cope with extremes by measuring how their cells respond in the lab to changing culture conditions that mimic real-world variation. This will provide a foundation for developing mathematical models to understand the genetic components of this tolerance, and why the response differs between species. This project will provide active learning and research opportunities for middle school, undergraduate and graduate students, including many from historically underserved populations. It will develop sixth grade curricular enrichment in biology and computer coding, provide opportunities for undergraduate students to participate in laboratory research, and support graduate students and postdoctoral researchers. Through cross-institutional collaborations, it will establish mentoring relationships between students at different levels. This project will also develop and disseminate outreach materials for the general public.Most mammals lie somewhere between the extremes of strict and flexible homeostasis, meaning that they tolerate fluctuations in cellular biochemical conditions to varying degrees. Some species tolerate extreme variation in cellular conditions, often for environmental factors that are specific to each organism. Conversely, variation in cellular conditions is poorly tolerated by many other species, including humans. This project will apply a common-garden framework to cultured cells from diverse mammals to uncover epigenetic responses that render cells of diverse species robust to variation in the internal milieu. RNA-seq, ATAC-seq, and cellular morphology and physiology data will be used to assay the responses of cells from different species when exposed to a panel of variable oxygen, glucose, and temperature conditions. By analyzing these datasets using new comparative computational approaches and an evolutionary framework, the project will identify genes involved in strictly homeostatic versus flexible cellular phenotypes. These genes will be modeled as “agents” in an agent-based modeling approach to distinguish between a "driver" hypothesis, with robustness coordinated by a few epigenotypes of large effect, or an alternate "small-impact" hypothesis, with robustness arising from many epigenotypes of individually small effect, and between the possibility of few versus many evolutionary paths to a given robustness phenotype. This cross-disciplinary collaboration will pioneer a new strategy to discover the nature — and limits — of cellular buffering abilities that underlie extreme phenotypes and reveal the "rules" whereby mammalian cells cope with environmental variation.This project is funded by the Understanding the Rules of Life: Epigenetics Program, administered as part of NSF's Ten Big Ideas through the Division of Emerging Frontiers in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将研究管理不同物种在细胞水平上如何改变环境的生物学规则，以及某些物种比其他物种更强大的情况。所有物种都会遇到环境变化，但是有些宽容对大多数其他物种都是危险的。水果蝙蝠在喂养和飞行之间承受血糖的急剧变化，骆驼在炎热的沙漠环境中耐受高体温，而深水哺乳动物在长潜水期间很少有氧气生存。该项目的目的是通过衡量其细胞在实验室中对不断变化的文化条件的反应来了解各种物种如何应对极端。这将为开发数学模型以了解这种耐受性的遗传成分以及为什么反应区分物种之间的基础。该项目将为中学，本科生和研究生提供积极的学习和研究机会，其中包括许多历史悠久的人口。它将在生物学和计算机编码方面发展六年级，为本科生参加实验室研究，并为研究生和博士后研究人员提供帮助。通过跨机构的合作，它将在不同级别的学生之间建立关系。该项目还将开发并为公众开发外展材料。大多数哺乳动物位于严格和灵活的稳态极端之间，这意味着它们忍受在不同程度上的细胞生化条件下的波动。一些物种耐受细胞条件的极端变化，通常是针对每个组织特有的环境因素。相反，包括人类在内的许多其他物种（包括人类）的细胞条件变化差异很差。该项目将对来自潜水员哺乳动物的培养细胞应用一个共同的框架，以发现表观遗传反应，从而使潜水员物种的细胞适合内部环境变化。 RNA-SEQ，ATAC-SEQ和细胞形态和生理数据将用于断言来自不同物种的细胞的反应，当暴露于一组可变的氧气，葡萄糖和温度条件下。通过使用新的比较计算方法和进化框架分析这些数据集，该项目将识别与严格稳态和柔性细胞表型有关的基因。这些基因将在基于代理的建模方法中以“驱动器”假设的区分为“试剂”，以较大效果的几种表观型或一种替代性的“小影响”假设协调的“驱动程序”假设，以及由多个表观型的小小观效果，几乎不适合多个进化的态度而产生的，具有鲁棒性的鲁棒性。这种跨学科的合作将在细胞缓冲能力中发现一种新的策略，以发现极端表型的性质和局限性，这些能力是极端表型的基础，并揭示了“规则”，从而使哺乳动物细胞应对环境变化。该项目由理解的生活规则：表观遗传学计划，由nsf的专业人士进行，由生命的领导者进行管理。反映了NSF的法定任务，并通过使用基金会的知识分子和更广泛的影响审查标准评估被认为是宝贵的支持。