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

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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.