Collaborative Research: Towards an Integrative Mechanistic Theory of Within-Host Disease Dynamics

奖项：DMS 0342388,0342239,0342325主要研究人员：杨光，Val Smith，Marilyn S.Smith这个多校区团队正在研究单个生物宿主内的过程，可以用生态化学计量学的模型来描述，生态化学计量学是研究生态相互作用中能量和多种化学资源(通常是元素)的平衡。这些概念被扩展到生物化学计量学，这已被证明是一个重要的新透镜，通过它我们可以观察和理解复杂的生物相互作用。在这一一般理论中，生物体及其组成细胞对能量和多种营养物质的循环和利用占据了核心地位。化学计量理论强调元素物质的流动，如碳、氮和磷，涵盖了多种生物尺度。它还允许通过严格的物理和化学约束来构建健壮的机械模型和预测模型。生物化学计量学最初是在湖泊学和植物生态学领域中形成和验证的，最近已在生理范围内应用于生物体发育和肿瘤生长等不同领域。在这项建议中，我们的目标是在内科疾病的大框架内综合和应用生物化学计量学的理论和经验方法。最近引人注目的发现将营养因素与疾病动力学联系起来，这表明越来越需要基于化学计量学的内部疾病数学模型，以跟踪潜在资源有限的影响。这项拟议的工作将理论研究和实验研究的线索编织在一起。我们的主要目标是构建可预测和可验证的理论模型，这些模型可以开始明确地处理宿主疾病动力学中化学计量相互作用的影响。这样的模型将以模块化的方式建立，从简单的确定性模型开始，然后逐渐添加随机性、空间异质性和遗传学。在每一步，模型都将通过体外实验室实验进行挑战、校准和测试。拟议的工作将在科学研究和教育方面产生广泛影响，并最终在内部疾病管理和治疗方面产生广泛影响。关于前者，我们的研究团队是三个跨学科的，小组成员包括数学、理论物理、生态学和生物医学。我们的合作努力将为不同民族/种族背景的本科生和研究生以及初级科学家提供在跨学科交流和探索方面的第一手教育经验。目前的提案是朝着理解疾病的新方法迈出的一步，旨在开发强大的、经过实验校准的疾病-宿主相互作用的数学理论，这些理论可以应用于各种疾病。我们坚信，这些理论在目前和未来的研究中都将发挥核心作用。这些资助是根据DMS/NIGMS支持数学生物学领域研究资助的联合倡议为三个机构提交的合作提案提供的。这是一项由国家科学基金会的数学科学部和生物科学局以及国家卫生研究院的国家普通医学研究所(NIGMS)主办的联合竞赛。

AbstractAwards: DMS 0342388, 0342239, 0342325Principal Investigators: Yang Kuang, Val Smith, Marilyn S. SmithThis multi-campus team is studying processes within a singlebiological host that can be described by models inspired by ecologicalstoichiometry, the study of the balance of energy and multiplechemical resources (usually elements) in ecologicalinteractions. These concepts have been broadened by their extension tobiological stoichiometry, which has proven to be an important new lensthrough which we can view and understand complex biologicalinteractions. Within this general theory, the cycling and utilizationof energy and multiple nutrients by organisms and their constituentcells occupies a central position. With its emphasis on the flow ofelemental matter, such as carbon, nitrogen, and phosphorus,stoichiometric theory covers multiple biological scales. It alsoallows, via rigid physical and chemical constraints, the constructionof robust mechanistic and predictive models. Originally formulated andverified in the fields of limnology and plant ecology, biologicalstoichiometry has recently been applied at physiological scales tosuch diverse areas as organism development and tumor growth. In thisproposal we aim to synthesize and apply theoretical and empiricalapproaches to biological stoichiometry within the grand framework ofinternal disease. Recent headline-grabbing findings that connectnutritional factors to disease dynamics indicate there is anincreasing need for stoichiometry-based mathematical models ofinternal disease that track the effects of potentially limitingresources. The proposed work weaves together threads of theoreticaland experimental research. Our primary aim is the construction ofpredictive and verifiable theoretical models which can begin toexplicitly deal with the effects of stoichiometric interactions inwithin-host disease dynamics. Such models will be built in a modularfashion, starting with simple deterministic models, and thenprogressively adding stochasticity, spatial heterogeneity, andgenetics. At each step the models will be challenged, calibrated, andtested by in vitro laboratory experiments.The proposed work will have a broad impact in both science researchand education, and eventually in internal disease management andtreatment. Regarding the former, our research team is trulyinterdisciplinary, with group members in mathematics, theoreticalphysics, ecology, and biomedicine. Our collaborative efforts willprovide undergraduate and graduate students and junior scientists ofdiverse ethnic/racial backgrounds with first-hand educationalexperience in cross-disciplinary communication and exploration. Thecurrent proposal is a step towards new ways to understand disease,aiming to develop robust and experimentally calibrated mathematicaltheories of disease-host interactions that can be applied to a widevariety of diseases. We firmly believe that such theories have acentral role to play in present and future research. These grants forproposals submitted as a collaborative proposal from threeinstitutions are made under the Joint DMS/NIGMS Initiative to SupportResearch Grants in the Area of Mathematical Biology. This is a jointcompetition sponsored by the Division of Mathematical Sciences and theDirectorate for Biological Sciences at the National Science Foundationand the National Institute of General Medical Sciences (NIGMS) at theNational Institutes of Health.