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

[摘要]奖项：DMS 0342388, 0342239, 0342325首席研究员：Yang Kuang， 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，这些过程可以通过受生态化学计量学启发的模型来描述，研究生态相互作用中能量平衡和多种化学资源（通常是元素）的研究。这些概念已经被扩展到生物化学计量学，这已经被证明是一个重要的新镜头，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着中心地位。化学计量学强调元素物质（如碳、氮和磷）的流动，涵盖了多个生物尺度。它还允许通过严格的物理和化学约束，构建强大的机械和预测模型。生物化学计量学最初是在湖沼学和植物生态学领域提出和验证的，最近在生物发育和肿瘤生长等不同领域的生理尺度上得到了应用。在这个建议中，我们的目标是综合和应用理论和经验的方法，生物化学计量学在内部疾病的大框架内。最近的头条新闻发现，营养因素与疾病动力学的联系表明，越来越需要基于化学计量学的内部疾病数学模型，以跟踪潜在有限资源的影响。这项提议的工作将理论和实验研究的线索编织在一起。我们的主要目标是建立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，然后逐步增加随机性、空间异质性和遗传学。在每个步骤中，模型将受到挑战，校准，并通过体外实验室实验进行测试。这项工作将对科学研究和教育产生广泛的影响，并最终对内部疾病的管理和治疗产生广泛的影响。对于前者，我们的研究团队是真正的跨学科，团队成员来自数学、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、研究生和初级科学家提供跨学科交流和探索的第一手教育经验。目前的提议是朝着理解疾病的新方法迈出的一步，旨在开发可应用于各种疾病的疾病-宿主相互作用的稳健和实验校准的数学理论。我们坚信，这些理论在当前和未来的研究中发挥着核心作用。这些资助是由三个机构作为合作提案提交的，是在DMS/NIGMS联合倡议下提供的，以支持数学生物学领域的研究资助。这是一项由美国国家科学基金会数学科学部和生物科学理事会以及美国国立卫生研究院国家普通医学科学研究所（NIGMS）联合主办的竞赛。

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.