M Denise Dearing - US grants

9809961 Dearing A fundamental goal in the study of the ecology of mammalian herbivores has been to identify the physiological factors that limit dietary specialization. Although plant secondary compounds have played a paramount role in the generation of diet selection hypotheses of mammalian herbivores and detoxification capability is often proposed as a mechanism determining diet breadth, our understanding of how herbivores detoxify secondary compounds is quite limited. To generate diet selection models with more predictive power and to understand the ecological distributions of herbivorous mammals, we first need to improve our knowledge of the mammalian detoxification system. The objective of the proposed research is to identify and quantify the mechanisms that specialist and generalist herbivores use to detoxify plant secondary compounds by testing the following 3 hypotheses: by producing detoxification metabolites that are less acidic than those produced by generalists; by generating the same acid-load during detoxification as generalists, however, eliminating hydrogen ions (H+) produced in this process through an entirely different route than generalists; and by having a greater capacity to buffer urine than generalists.

Mammals that consume plants run the risk of being poisoned by naturally occurring toxins produced by plants. Little experimental work exists on the mechanisms mammals employ to deal with plant toxins, or how specialized species such as the koala are capable of consuming plants that are toxic to other species. The proposed research interfaces with ecology, chemistry, physiology and pharmacology to address mechanisms by which herbivores detoxify plant toxins as well as the costs of detoxification. The PI will investigate how woodrat herbivores that specialize on one species of toxic plant differ in detoxification physiology from generalist woodrats that consume a variety of plant species. Woodrats are a model system for this problem because the diversity of specialists and generalists woodrats is unparalleled by any other genus of mammalian herbivores. Thus far, the PI has found that specialist herbivores are capable of tolerating higher doses of toxins than generalists. Contrary to conventional wisdom, specialists do not appear to have unique detoxification pathways compared to generalists but rather systems with a greater capacity. Preliminary results suggest that specialists are able to deal with high toxin loads because they can eliminate toxins faster than generalists. These studies will further investigate how specialists and generalists differ in detoxification abilities and will address issues on costs and constraints of dietary specialization. For example, are specialists more efficient than generalists in processing toxins? Do specialist herbivores trade-off the ability to detoxify a wide range of toxins in exchange for enhanced processing of a subset of toxins?
In this century, mammalian herbivores will confront profound detoxification challenges. Novel toxins (eg dioxins, PCBs) are being added to the environment at unprecedented rates. Moreover, in the next 50 years, levels of CO2 in the atmosphere are predicted to double due to extensive burning of fossil fuels. Many species of plants grown under elevated levels of CO2 are substantially inferior in nutritional quality in that they are lower in protein and contain up to twice the toxin concentration as plants grown under current CO2 concentrations. Will mammalian herbivores be aversely impacted by such a radical change in the nutritional quality of their food, particularly the increase in toxins? The results of this research on detoxification processes of wild herbivores will provide vital insights on how herbivores will be affected by this change in nutritional quality of food.

Abstract

DEB-0129299
M. Denise Dearing

Workshop: Proposal for Conference on the History of Atmospheric CO2 and its Effect on the Evolution of Plants, Animals, and Ecosystems

Several new proxies to estimate the concentration of atmospheric CO2 have been developed in the last few years so that our understanding of the history of CO2 in the atmosphere is much improved. Plant growth is strongly influenced by the concentration of atmospheric CO2, causing changes in nutrient status and the production of plant toxins, and affecting the competition between plants using different photosynthetic pathways or having different physiological strategies. Changes in availability, nutrient content, or toxicity of certain plants impacts animals at the ecosystem level. Therefore, atmospheric CO2 can be considered to be a driver of evolution at the ecosystem level. The time is now ripe for a synthesis of recent work that links the history of atmospheric CO2 to evolution at the ecosystem level. This grant will support an international symposium to address this topic.

Limitations of the detoxification system in processing plant toxins are implicated as the mechanism explaining the paucity of dietary specialization among mammalian herbivores. In fact, little is known about how wild herbivores metabolize plant toxins and how detoxification restricts dietary specialization. Detoxification constraints are of current interest given that the toxin concentrations of many plants will double within the next century due to rising atmospheric CO2 levels. The overarching goals of the research are to understand the mechanisms that permit and tradeoffs associated with dietary specialization in herbivorous woodrats (Neotoma). Specialist woodrats are predicted to absorb lower concentrations of plant toxins compared to generalists. The research examines 3 mechanisms that may decrease toxin absorption: 1) tannin-binding proteins 2) p-glycoproteins and 3) intestinal detoxification. Specialists and generalists will be compared to determine how they differ with respect to these mechanisms. Biochemical and pharmacological methods will be employed. In addition, theory predicts that specialists have detoxification systems that are more efficient in processing plant toxins in their diet compared to generalist herbivores processing the same compounds. However, the superior ability that specialists have in processing toxins from their diet is predicted to compromise their efficiency to biotransform novel toxins, which are not contained in their normal diet. The potential tradeoffs of dietary specialization will be addressed by comparing 1) maximal levels of novel toxins that specialists and generalists can ingest; 2) capacities of detoxification pathways (functionalization and glucuronidation) using probe drugs; and 3) surveying the detoxification systems of generalists and specialists with DNA microarrays. For the education component, an intensive course is proposed for mid-level students (sophomore-junior) to train them in various aspects of research by using this research project as the example and opportunity. This course, "Scientific Immersion", will be offered in the fall semester each year to a maximum of five students.

Sin Nombre hantavirus (SN) is a recently discovered virus carried by deermice that causes disease with high mortality in humans. Several recent studies have proposed that human disturbance of habitat significantly affects the number of deermice infected with SN. Given unprecedented rates of disturbance and limited understanding of the mechanisms governing variation in SN infection, a thorough study of how disturbance affects SN dynamics is warranted. The central focus of the proposed study is to determine how human disturbance affects SN prevalence in deermice and other reservoirs. To address this issue, a multifaceted research program is proposed that includes empirical and theoretical work. The field data will be used to determine the underlying mechanisms responsible for differences in prevalence. These ground-based data will be used to generate predictive mathematical models of prevalence using aerial and satellite images.

The broader impacts of this study include education, interdisciplinary research and national security. Several undergraduate and graduate students will be trained as part of this research. The project unites scientists from diverse fields (geography, mathematics, ecology, virology). Lastly, the research will yield critical information on the biology of Sin Nombre virus, which is listed as a biological agent of concern for national security.

Principal Investigators: Dr. M. Denise Dearing, Dr. Kirk Thomas

Project Number: IOS-0817527


TITLE: Functional Genomics of a Dietary Shift in a Mammalian Herbivore: Creosote Feeding in Neotoma lepida


For mammals that consume plants, one of the greatest challenges in shifting from one diet to another is the detoxification of novel plant toxins. We propose to advance our knowledge of the mechanisms used by mammalian herbivores by capitalizing on population differences in the feeding behavior of the desert woodrat. Approximately 11,000 before present, populations of desert woodrats occupying what is now the Mojave desert, underwent a major shift from feeding on a diet of juniper to that of a natural invader, creosote. Populations of woodrats that currently live in the Mojave have adapted to highly toxic creosote as evidenced by their ability to ingest greater quantities of creosote compared to populations that have no prior experience. In this project, the investigators will determine the underlying mechanisms for this difference in ability to process creosote. The investigators will use a combination of approaches from pharmacology and molecular ecology as well as cutting edge genomics techniques. The investigators expect to find specific liver enzymes that convey the ability to consume creosote toxins. The differences in liver enzymes between woodrats may be valuable in explaining differences among human populations in the metabolism of pharmaceutical and nutraceutical compounds. This work will promote the understanding of how mammals adapt to radical changes in diet after natural climate change. The data can be extrapolated to predicting how woodrats will respond to current and future climate change. One of the broader impacts is a contribution to scientific infrastructure in the form of a transcriptome of a non-model organism that will be available to other scientists. The investigators are committed to scientific outreach and participate in one or more outreach events annually in the community (e.g., science fairs, public lectures). The project will provide cutting edge, interdisciplinary training for a postdoctoral fellow, graduate students, undergraduates, summer high school students and for an assistant professor from an undergraduate institution. Trainees on this project will come from underrepresented groups in science, e.g., women and ethnic minorities.

PROJECT ABSTRACT FOR UTAH GK-12 GRANT

The Think Globally, Learn Locally: Neighborhood Ecology in a Global Perspective (TGLL) program is a collaboration involving graduate students and faculty from the Departments of Biology, Geology & Geophysics, Atmospheric Sciences (formally Meteorology) and the Utah Museum of Natural History, together with teachers and students from elementary schools in the Salt Lake City School District. TGLL will train 9 Graduate Fellows per year to develop and lead Inquiry-Based Activities (IBAs) for fourth, fifth and sixth grade students. These activities will focus on five major environmental issues: (1) habitat alteration, (2) pollution and disturbance, (3) invasive species, (4) climate change, and (5) disease. Students will learn the science behind these issues, their practical implications, and how individual lifestyle choices scale up to affect the relevant processes on a global scale. TGLL Fellows will serve as scientific role models and mentors to young students at a critical stage of their intellectual and emotional development, and will show them how to become citizen scientists with the outlook and preparation needed to engage productively with complex, emerging environmental issues.
The TGLL program will make science accessible to a wide audience by targeting schools and neighborhoods with high minority populations and actively recruit TGLL Fellows from underrepresented groups. The IBAs developed in the TGLL program will be integrated with the Science Core Curriculum of the State of Utah for fourth, fifth and sixth grades. By working with TGLL Fellows K-12 teachers will gain confidence in scientific teaching, and become active members of a research and teaching network.

This symposium at the annual meeting of the Society for Integrative and Comparative Biology will bring together prominent researchers working in the areas of eco-immunology and disease ecology and to provide a forum to review research in their respective subfields. It will foster collaborations across fields through the discussion of philosophical and empirical research approaches, and generate ideas on how to best utilize current technologies to address the common questions. Disease resistance is a function of pathogen dynamics including prevalence and virulence (disease ecology), but is also driven by the internal physiological state of an individual, including host immune function (eco-immunology). Despite the interconnectedness between the two disciplines the majority of research has focused on only one level of analysis, either ultimate (evolution and ecology of parasites and their effects on life histories) or a proximate (how environmental variables affect immune responses). However, the effects of ecological and evolutionary factors on susceptibility to disease are driven not only by environmental variation in diseases and their vectors but also by differences in host immune function that alters disease susceptibility across individuals. The goal of the symposium is to critically review recent advances in the disciplines of eco-immunology and disease ecology, and to integrate both the proximate and ultimate perspectives into a common theoretical framework.

Some of the most important interactions that facilitate mammalian life are between mammals and the diverse communities of microbes that reside within their digestive tracts. Mammalian herbivores in particular exhibit the most diverse gut microbial communities, which are thought to conduct fiber fermentation and other nutritional processes to benefit the host. However, in addition to fiber, plants also produce plant secondary compounds that act as anti-herbivore defenses. It has long been proposed that mammalian herbivores might also house microbes that detoxify these toxic compounds. This proposal aims to advance our knowledge of the microbes that live within the guts of a group of herbivorous rodents: woodrats. Woodrats hold tremendous promise for understanding diversity and for discovery of novel detoxifying microbes and genes, as they feed on a variety of plants containing toxins that likely have shaped gut microbial diversity. Indeed, microbes do allow woodrats to consume plant toxins, and the consumption of these toxins strongly changes their gut microbial communities. The central objective of the proposed research is to understand the biodiversity and community ecology of the gut microbiota in herbivores with respect to dietary toxins. The research will specifically investigate how evolutionary history and exposure to dietary toxins influence the community genetics of foregut microbes in a wild herbivore, and how dietary toxins might alter resident gut microbial communities and allow for invasion by a novel community.

This project will support the training of a graduate student in the emerging field of microbial metagenomics. In addition, high school and undergraduate students will be involved in the research and receive mentoring in the conduct of independent research. This project will support the development of an inquiry-based lecture geared towards the public, which will be presented at local schools and museums. Results from this research will identify important microbial genes associated with the detoxification of plant toxins, which could be useful in agricultural systems, especially in developing areas where livestock often need to feed on plants containing such toxins.

At every meal, thousands of species of plant-eating mammals confront the possibility of being poisoned by the natural toxins produced by their food. The generalized foraging habit of mammalian herbivores, eating many different plant species on a daily basis, is thought to result from limitations of their liver enzymes. Generalists are hypothesized to have a "jack of all trades" style of detoxification system that consists of liver enzymes able to metabolize a wide array of plant toxins but with low catalytic efficiency. In contrast, specialists are thought to have detoxification enzymes with enhanced efficiency towards a restricted number of toxins. This concept of biochemical tradeoffs with respect to dietary specialization has essentially become dogma without any experimental support. This research will capitalize on the extensive knowledge of mammalian detoxification enzymes gained from studies of drug metabolism in model species and humans, as well as on the availability of a superlative wild rodent model of mammalian herbivory. The long-term objective is to determine how dietary exposure to plant toxins has shaped the mammalian detoxification system through a focused study of liver enzymes in the cytochrome P450 subfamily 2B (CYP2B) in herbivorous woodrats (Neotoma).

The specific goals of this collaborative research are:
1.) Characterize the CYP2B enzymes in woodrats at the amino acid level.
2.) Use new metabolomic approaches to identify key P450 substrates in diets of woodrats and compare metabolism of plant toxins by woodrat CYP2B enzymes.
3.) Conduct structure-function analyses using site-directed mutagenesis and X-ray crystallography of woodrat CYP2B enzymes.

The work will address a longstanding hypothesis by drawing upon cutting-edge biochemical and structural biology approaches to generate the first detailed examination of CYP2B enzymes of wild herbivores, identify substrates, and compare enzyme function. The ultimate goal is to solve the crystal structures of woodrat enzymes in complex with plant toxins. Currently, knowledge of detoxification enzymes of mammals is rudimentary. The work has the potential to contribute to the understanding of drug metabolism in humans given preliminary data of these investigators on woodrat enzymes. In addition, woodrats are nature's historians; their behavior of storing food has facilitated an understanding of the natural changes that have taken place in the desert southwest over the last 35,000 years. An interactive display about the ecology of woodrats and their importance to society will be developed at the Utah Museum of Natural History. The PIs will mentor a new generation of trainees (high school students through postdoctoral fellows) in interdisciplinary research. This award is co-funded by the Chemistry of Life Processes Program in the Division of Chemistry.

Some of the most critical interactions facilitating mammalian life occur between mammals and the diverse communities of microbes that reside within their guts. Plant-eating mammals harbor the most diverse microbial communities. Many of these microbes are important in the degradation of fiber; however, gut microbes may also play an essential role in detoxifying the natural toxins common in plants. This project will investigate how host evolutionary history and dietary toxins shape the diversity of the gut microbiome of herbivorous mammals by focusing on a group of rodents that specialize in eating plants that are toxic to other animals. Woodrats have an unusually toxic diet spanning a broader array of plants than most species. This makes them a potential model system for insight into this poorly understood but clearly important role of biodiversity in allowing animals to cope with plant defenses. The objectives of this project are to 1) identify and compare the microbial communities across chambers of the rodent gut to understand their function 2) investigate the influences of evolutionary history and dietary toxins in sculpting microbial diversity and function; 3) determine how diversity interacts with the liver of the host to facilitate detoxification. This project will provide some of the first insights into the microbial diversity of wild herbivores and the role that plant toxins play in shaping diversity.

This work will advance our understanding of microbial diversity and may reveal new microbes useful for human probiotics. The discovery of novel microbes and genes associated with detoxification is anticipated; such biological material is of great interest to agricultural scientists wishing to improve husbandry practices in livestock. A one-week summer workshop will be offered annually to middle school students to teach concepts of microbial diversity through the development of interactive computer simulations and games.

The vast diversity and number of microbes that reside on other organisms, i.e., the "microbiota", are increasingly being recognized for their importance in the health and well-being of their host organisms. For the most part, scientific studies on the interactions between microbes and their hosts have largely been focused on humans or model species (e.g., laboratory mice) in an effort to understand issues related to human health. However, research into roles that microbes play in the ecology and physiology of their host is a rapidly growing area, and one that has much to contribute to human health and agricultural practices. The organizers will host a symposium that brings together a number of scientists that investigate host-microbe interactions at the Society for Integrative and Comparative Biology's annual meeting January 4-8, 2017. Nine speakers and the two symposium organizers have been invited to present seminars discussing their research programs. The organizers have made efforts to broaden participation in this meeting by inviting seven female speakers and two racial/ethnic minorities. In addition to the research presentations, the organizers will host a 3-hour workshop discussing the tools, techniques, and challenges of microbiome research in integrative and comparative biology. This symposium will expose researchers in SICB to these methods.

Recent studies have revealed that animals are not individuals but rather are "holobionts" that host highly diverse and interactive communities of microbes. These microbial communities provide a number of services and functions to their hosts. For the most part, investigations in the host-microbial interactions have been focused on humans or model systems targeted at human health. However, research into roles that microbes play in the ecology and evolution of their host is a rapidly growing area. The organizers will host a symposium that brings together a number of researchers that investigate host-microbe interactions, which also spans the interests of members of the Society for Integrative and Comparative Biology (SICB). This meeting will take place in conjunction with the annual meeting of SICB in New Orleans, LA, from January 4-8, 2017 and is organized by Dr. Denise Dearing (University of Utah) and Dr. Kevin D. Kohl (Vanderbilt University). Nine speakers and the symposium organizers have been invited to present seminars discussing their research programs. The organizers have made efforts to broaden participation in this meeting by inviting seven female speakers and two racial/ethnic minorities. In addition to the research presentations, the organizers will host a 3-hour workshop discussing the tools, techniques, and challenges of microbiome research in integrative and comparative biology. This will expose researchers in SICB to these methods. Results from this meeting and workshop will be published in the journal Integrative and Comparative Biology.

At every meal, animals that feed on plants (herbivores) such as deer, cattle, and rabbits, face the possibility of being poisoned by naturally-occurring toxic chemicals in their food. Nevertheless, how herbivores process natural toxins remains poorly understood. For example, remarkably little is known about the specific genes that control an animal's ability to process potentially toxic compounds in plants. To address these fundamental problems, this research will focus on a dramatic dietary change: woodrats normally eat juniper and cactus, but several populations in the American southwest have switched to a diet of creosote bush. Creosote bush produces natural toxins that radically differ from juniper and cactus, and therefore the specialized woodrat populations must detoxify their diets differently than the juniper and cactus-eaters. The goal of this project is to identify DNA-level changes that are associated with woodrats' ability to feed on a toxic diet of creosote bush. This project will develop new genomic tools that will be useful to the broader scientific community. A better understanding of how animals process toxins can also impact decisions about pharmaceutical development for humans and other animals, and influence feeding options to improve production of free-ranging domestic herbivores like cattle. Results of this work will be communicated to the public through an interactive display about the ecology of woodrats at the Utah Museum of Natural History.

Despite decades of pharmacological research on model species and humans, the mechanisms used by mammalian herbivores to metabolize plant secondary compounds and the genomic basis underlying adaptation to new diets remain poorly understood. This research will investigate the evolution of dietary adaptation and specialization in mammalian herbivores by capitalizing on a dramatic diet change event: the replacement of juniper (Juniperus spp.) and cactus (Opuntia spp.) with creosote bush (Larrea tridentata) in the diets of herbivorous woodrats. The project has three goals: 1) Identify genomic changes associated with a radical dietary shift in Neotoma lepida. 2) Test for the repeated involvement of similar genetic pathways for specialization on creosote diets in N. bryanti. 3) Characterize the transcriptomic response of parental and hybrid populations of N. lepida and N. bryanti to a creosote diet. The proposed work leverages modern evolutionary genomic approaches to address a long-standing question in physiological ecology: which mechanisms are important in the processing of toxic diets? The project will lead to a deeper understanding of the responses of organisms to changes in the environment, including fundamental information at the genomic level about how mammalian herbivores adapt to dietary toxins. The project specifically tests whether the same genomic regions are under selection in two species that independently evolved the ability to specialize on creosote diets. An interactive display about the ecology of woodrats and their importance to society will be developed in collaboration with the Utah Museum of Natural History. Genomic tools will be developed that will be useful to the broader scientific community. In addition, the PIs will mentor students (high school through graduate) and postdocs in physiological genomics research on non-model species.