Colin K. Combs - US grants

One of the histological findings necessary for making a diagnosis of Alzheimer's disease (AD) is the cytoskeletal pathology termed the neurofibrillary tangle (NFT). The microtubule associated protein, tau, is the primary component of the NFT. Attempts to define a mechanism of NFT formation often focus on site specific phosphorylations of tau protein. These have been described in postmortem tissue primarily in developing and AD affected brains and are thought to be a preliminary event in the formation of the tangle. Study of the developmental regulation of tau's Alzheimer epitope phosphorylations may help explain their persistence or recurrence during the pathogensis of AD. To begin examining the developmental tau phosphorylations, we have used rat embryonic hippocampal cultures. Using phosphorylation dependent anti-tau antibodies, a temporal phosphorylation of two Alzheimer epitopes has been seen during neuronal maturation in vitro. It should be possible to characterize potential kinase regulatory systems for these discreet phosphorylation events. Once these kinase actions have been identified, it will be reasonable to expect similar events to be recapitulated or maintained within neurons bearing hyperphosphorylated tau and NFTs in Alzheimer's Disease brain. Hypothesis I: Neurons express independent temporal phosphorylations of tau's AD epitopes during development in vitro. This can be addressed in the following manner: Aim 1: Tau's intracellular localization and temporal phosphorylation on selected Alzheimer epitopes in vitro will be defined using immunohistochemistry. This will be supported by Western blot analysis. Hypothesis II: It if further hypothesized that tau's specific phosphorylation state in developing neurons in vitro will correspond to expression and/or activation of specific kinases. This question will be answered by the following: Aim 2: The development expression of selected kinases will be compared to the temporal pattern of tau's site specific phosphorylations defined in Aim 1. This will be done using double-label immunofluorescent histochemistry. As additional evidence for the involvement of selected kinases in the regulation of tau phosphorylation, specific kinases will be pharmacologically inhibited in culture and tau phosphorylation state will be monitored for resulting changes via immunohistochemistry and Western blot analysis. Selected kinase activity assays will be necessary to determine the drug concentrations needed for maximal inhibition.

ABSTRACT NOT AVAILABLE

DESCRIPTION (provided by applicant): The purpose of this study is to explain the aberrant, elevated neuronal expression of two specific proinflammatory markers, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), in Alzheimer's Disease brains. Although increased expression of these proteins in AD is attributed to an "inflammatory" process occurring in the brain, neither the stimuli nor the consequences of this are known. Answering these questions will provide insight into the unknown mechanism of AD progression and ultimately help identify molecular targets for therapeutic neuroprotection. Previous studies demonstrate that neurotoxic beta-amyloid (Abeta) fibrils stimulate calcium influx in neurons. Elevated intracellular calcium is a potent stimulus for increased COX-2 expression in neurons. The proinflammatory cytokine, TNFalpha, is a well-described stimulus for increased iNOS expression in many cell types and is neuroprotective against Abeta fibrils. Preliminary data demonstrates that toxic Abeta fibril stimulation increases neuronal COX-2 expression in mouse cortical neuron cultures. Neuroprotective TNFa stimulation increases neuronal iNOS expression. These data suggest the hypotheses that COX-2 activity is required for Abeta-dependent toxicity in AD and iNOS activity is required for TNFa-dependent neuroprotection from Abeta fibrils. The following specific aims will address this hypothesis: 1) Quantitate the increase in COX-2 mRNA and/or protein level following toxic Abeta peptide stimulation of primary mouse cortical neuron cultures and determine whether COX-2 activity is required for the Abeta toxicity. Specific inhibitors of COX-2 activity will be tested for their ability to attenuate neuron death in the presence of Abeta fibrils. 2) Quantitate the increase in iNOS mRNA and/or protein level during TNFa-mediated neuroprotection from Abeta toxicity in cortical neuron cultures. Specific inhibitors of iNOS activity will be used to determine whether iNOS activity is required for the TNFalpha-dependent protection from AB fibrils.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic neurodegenerative disease affecting over four million Americans. It is characterized histologically by intracellular neurofibrillary tangles and extracellular aggregates of amyloid peptide containing plaques. In addition, AD brains display robust microglial and astrocyte reactivity. Our long term goal is to identify strategies for limiting microglial activation in the AD brain as a means to prevent inflammatory mechanisms of disease progression. The specific hypothesis of this proposal is that the pre- aggregated, or oligomeric, amyloid peptide stimulates microglial activation in a fashion requiring expression of the parent amyloid precursor protein (APP). This suggests the possibility that APP is a proinflammatory receptor that is activated through formation of its own proteolytic amyloid peptide. We base this hypothesis on the following observations: 1) simulation of ligand binding by antibody cross-linking APP on the surface of microglia or a monocyte cell line stimulates activation of a tyrosine kinase based signaling cascade responsible for increased proinflammatory protein expression;2) stimulation with oligomeric peptide results in a similar profile of tyrosine kinase activation and proinflammatory protein expression;3) oligomer peptide stimulation of microglia and the monocytic cell line is dependent upon expression of APP;and 4) oligomer stimulation of microgliosis and synaptic loss in vivo in mouse brains is also dependent upon expression of APP. Based upon these data, the experimental focus of this application we will define the nature of the APP requirement for oligomer stimulation by determining whether APP is a component of a multireceptor signaling complex needed for oligomeric stimulation of microglia or whether oligomeric Abeta interacts with APP in a direct ligand-receptor fashion to mediate microgliosis. The specific aims will address this hypothesis in vitro in the following manner: 1) Define the role of APP in oligomer-dependent interaction with microglia and monocytes. We will define whether oligomer stimulation results in A) multimerization of APP and/or B) recruitment of APP into a multi- receptor complex. We will also define whether oligomer directly interacts with APP in a classic receptor- ligand fashion. 2) Define the reactive microglial and monocytic phenotype stimulated by oligomeric peptides. We will define the APP dependent signaling response initiated by oligomer stimulation. We will also define the APP dependent secretory profile following oligomer stimulation. Specifically, we will quantitate secretion of specific proinflammatory cytokines and Abeta as well as effects on neuron toxicity.

Age; Alzheimer beta-Protein; Alzheimer's amyloid; Amyloid Alzeheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Fibril Protein (Alzheimer's); Amyloid Protein A4; Amyloid beta-Protein; Amyloid beta-Protein, Alzheimer's; CRISP; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Peptides; Phagocytosis; Phenotype; Research; Research Personnel; Research Resources; Researchers; Resources; Source; United States National Institutes of Health; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; receptor expression; response; soluble amyloid precursor protein

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is estimated to affect over 5 million Americans. A significant risk factor for AD is particularly mid-life obesity. In itself, obsity also represents a tremendous health concern for the U.S. with its suggested epidemic levels. Therefore, any strategy to ameliorate either or both conditions is extremely attractive therapeutically. We propose that the relationship between AD and obesity is not correlative but that there may be a common pathophysiology. It is well known that mutations in the gene coding for amyloid precursor protein, APP, are responsible for autosomal dominant forms of AD. However, our preliminary data indicates that APP is critically required for weight gain and the associated brain and adipose changes that occur in a murine model of high fat diet-induced obesity. APP expression is actually required for efficient uptake of fatty acids into cells. Therefore, we hypothesize that APP regulates diverse cellular differentiation involving, in particular, changes in lipid metabolism that regulates adipocytes, neurons, and macrophage/microglia during diet-induced obesity. Dysregulation or alteration of this biology by mutant APP will have ramifications during obesity but, more importantly, during AD. We will first test this hypothesis quantifying the ability of wild type and mutant APP and any associated signaling or processing to regulate adipocyte, macrophage/microglia, and neuron phenotype in vitro. We will then define a role for APP in tissue specific changes during diet-induced obesity in vivo using wild type and mutant APP expressing mice compared to APP-/- mice. By defining the role of normal and mutant forms of APP in regulating cellular phenotype in adipose tissue depots and brain we will explain how APP contributes directly to diet-induced obesity and possibly to progression of AD. This not only offers a common mechanistic pathophysiology of these two diseases but also targets APP and its associated signaling response for therapeutic intervention.

DESCRIPTION (provided by applicant): Monocyte-endothelial interaction is presumed to be an early event in the atherosclerotic process. Therefore, a strategy to limit monocyte adhesion or diapedesis through reactive vessel endothelium should be effective at this early stage. This is a departure from current therapeutic efforts that attempt to modulate lipid metabolism or thrombus formation. Our preliminary data demonstrates that amyloid precursor protein (APP) is an appropriate protein on endothelial cells and monocytes for targeting early stage atherosclerosis. Although APP is often described in relation to Alzheimer's disease (AD), it is upregulated in a variety of cell types during a range of pathologies. We observed that atherosclerotic human and mouse endothelium in both aorta and brain upregulate APP expression where it appears to mediate a specific tyrosine kinase-based activation response in endothelial cells that regulates their activation and subsequent monocytic adhesion. These data suggest that APP contributes to monocyte adhesion in inflamed endothelium which can lead to atherosclerotic plaque formation in both peripheral and cerebral vasculature. This is a novel function for this protein implicating it as a possible target for therapeutic intervention during erly disease stages. We will test this idea by first demonstrating that APP is required for high-fat die dependent atherosclerotic plaque formation and vessel inflammation using the common murine model of atherosclerosis, apoE-/- mice, crossed to mice without APP (APP-/-). We will next use primary cultures of endothelial cells and monocytes to demonstrate the specific, APP-dependent interactions and subsequent phenotype changes that are regulated during cell-cell interaction. Defining a role for APP in atherosclerotic plaque formation represents an innovative component of this study. The impact from this work will not only identify a new disease mechanism and provide a function for APP but will also stimulate our group and others to develop APP inhibitor strategies for future therapeutics. We also expect this role of APP in regulating immune cell and vessel behavior will ultimately be directly relevant to mechanisms of AD.

? DESCRIPTION (provided by applicant): Although amyloid precursor protein (APP) is ubiquitously expressed, much of the focus on APP biology with respect to Alzheimer's disease (AD) has focused on the brain due to high levels of neuronal expression. However, the enteric nervous system of the gastrointestinal tract also expresses APP. Moreover, the gastrointestinal tract is filled with a plethora of immune cell types that broadly affect not only the function of te gut but also other organ systems including the brain. Recognition of this comparison forces one to consider whether or not Aß aggregation/deposition with subsequent inflammation characteristic of the brain during AD occurs in parallel in the digestive tract. This suggests an opportunity for peripherally monitoring APP-related biology or therapeutic interventions as well as a novel understanding of the pathophysiology of AD. Even more exciting is the possibility that the two organ systems influence disease phenotype in one another based upon not only immune cell interactions but also the direct autonomic innervation of the gastrointestinal tract. Our preliminary data using a transgenic mouse model of AD demonstrated increased APP levels, Aß deposition and immune dysfunction in the intestines similar to findings from brains. Moreover, manipulation of the peripheral immune system with therapeutic antibodies was sufficient to attenuate brain microgliosis in these mice. Most importantly, we observed APP immunoreactivity, Aß plaques, and phospho-tau containing tangles in AD large intestines validating the relevance of the mouse model. In comparison to human diseased intestines, we will continue using the most relevant mouse models of AD to define the temporal relationship between brain and gastrointestinal disease identifying both neuronal and immune changes in correlation with both memory performance and gut function. We will also determine the specific role of APP and its metabolites in regulating both intestinal epithelial and immune cell phenotypes. Finally, by altering gut-brain communication we will determine whether it is possible to regulate disease progression in either organ by manipulating immune or nervous communication.

Exposure to ambient air pollution has been associated with both cognitive impairment and cardiac dysfunction and a post-mortem study reported evidence of accumulation of amyloid among people living in cities with high levels of ambient pollution. Whether exposure to high levels of air pollution accelerates the formation of aggregates is unknown. We propose a 3 month controlled exposure experiment in Alzheimer?s prone mice carrying the single mutation in the in the Presenilin-1 gene (PSEN1) (PS1?E9) or the double mutation in the APPswe + the PS1?E9 (APPswe/PS1?E9). All mice are in the C57/Bl6J background and C57/Bl6J wild-type mice will serve as controls. Mice will be exposed beginning at age 3 months to evaluate the impact of concentrated fine particulate matter (PM2.5) versus filtered air (FA) exposure on brain and cardiac structure and function. Mice will be studied at two time points: immediately after the exposure and at the end of the 3-month exposure. Another set of mice will be exposed to PM2.5 for 3 month than for FA for 3 more months. A control group will be exposed to FA for 6 month. We hypothesize that Alzheimer?s prone mice exposed to PM2.5 will develop: 1) a greater quantity of aggregates in the specific anatomical regions of the brain and heart as assessed by imaging and electron microscopy; 2) worsen brain function assessed with behavioral studies and cardiac function assessed by echocardiography, biometric measurements in-vivo and worsen calcium homeostasis in primary neurons and contractile function and calcium handling in isolated cardiomyocytes in-vitro. We also hypothesize that exposure to PM will accelerate amyloid pathology by inducing oxidative stress.

Project Summary: This is an administrative supplement proposal in response to NIGMS Notice number (NOT- GM-21-029). The purpose of this supplement proposal is to replace an outdated confocal microscope in the Imaging Core with a state-of-the-art Leica Stellaris 5 confocal microscope to support and extend the goals of the Host-Pathogen COBRE program. Our existing 16-year old Zeiss 510 META confocal microscope, which reached its end of service life in 2016, is based on old technology and is beginning to experience repair issues. As a result, COBRE investigators are unable to undertake imaging approaches that are possible using the technology that exists in current state-of-the-art microscopes. Replacing this instrument with a Leica Stellaris 5 confocal microscope will ensure that investigators have the technology they require to support and advance their research goals. The overall goals of these projects are to understand the immunological processes and mechanisms that underly a range of host-pathogen interactions in diseases caused by viral, bacterial, and parasitic infections. All projects require high resolution, multichannel imaging of samples labeled with fluorochromes having excitation wavelengths ranging from 405 nm to 633 nm in fixed and live samples. Unlike the existing confocal microscope in the Imaging Core, which is effectively a 3-channel system with conventional PMT detectors, the Stellaris 5 confocal microscope is a prism-based four channel system, equipped with ultrasensitive Power HyD S detectors and offering an array of advanced imaging features including superresolution imaging. It will allow investigators to image samples labelled with four or more fluorescent labels, including dyes such as DAPI, which cannot be visualized using our existing instrument. The Stellaris 5 microscope will be integrated into our already functional Imaging Core in association with other imaging equipment and will take advantage of existing web-based scheduling, technical support, web-based data storage and sharing, system contract support, and a microscopic imaging service supported by telemicroscopy. Acquisition of this instrumentation will build institutionally on our very successful COBRE, INBRE, and DaCCoTA CTR programs. The Stellaris 5 confocal with superresolution and other advanced capabilities will advance biomedical science research capacity by Host-Pathogen COBRE investigators. It will also extend the research capacity of investigators affiliated with Epigenomics in Development and Disease COBRE, investigators affiliated with the DaCCoTA CTR, and other investigators in the UND SMHS, on the UND campus, and in the regional research community.

Project Summary The brain communicates with the gastrointestinal tract via the well-established gut-brain axis. Due to an increase in the permeability of blood brain barrier and intestinal epithelial barrier during aging, the brain likely becomes more susceptible to inflammation initiated in the gut. Both chronic inflammatory bowel disease (IBD including ulcerative colitis and Crohn's disease) and Alzheimer's disorder (AD) increase in prevalence among the elderly. However, the role of this intestinal inflammation on AD progression remains unclear. We observed a significant increase in intestinal inflammation and dysfunction during disease in a mouse model of AD. Based upon this data we hypothesize that AD includes intestinal dysfunction as a largely unrecognized component of disease. Moreover, we expect that chronic conditions such as IBD may potentiate progression of AD through inflammatory changes propagated from the intestines to the brain. We will elaborate the link between the intestines and the brain in AD using a transgenic mouse model of AD, AppNL-G-F mice. Our hypothesis will be tested by completing three aims. Aim one will use clinically available intestine-selective T cell inhibitory antibodies to attenuate basal AD intestinal inflammation and colitis-induced exacerbation in AppNL-G-F mice and confirm that intestinal dysfunction contributes to memory deficits in these mice. Aim two will assess the efficacy of the gut-selective inhibitory antibody therapy to decrease brain A? levels, gliosis, synaptic loss, and cytokine levels. The final aim will cross the AppNL-G-F mice to Ltatm1Dch mice that carry a null mutation in lymphotoxin ? resulting in absence of Peyer's patches and lymph nodes. This genetic approach will provide additional confirmation that intestinal inflammatory changes in the AppNL-G-F mice are required for the memory dysfunction and brain related changes. Completion of the study will verify a critical role of gut inflammation in disease progression and validate a clinically available therapeutic option, anti-?4?7 antibodies, as treatments targeting the gut-brain axis. This suggests that select immunomodulatory agents can be repositioned to combat the inflammatory component of AD without the need for crossing the blood brain barrier.

Summary: The objective of the Histology Core Facility at the University of North Dakota School of Medicine and Health Sciences, is to provide high quality instrumentation, sample preparation and training in a wide spectrum of fundamental and advanced histological techniques to COBRE research investigators. The Histology Core Facility will be located in the first level of the new UND SMHS Building adjacent to the established Imaging Core which consists of the multiphoton, confocal, intravital imaging, fluorescent, TIRF and electron microscopy suites. The Histology facility will be critical to the completion of the proposed scientific projects from the five junior investigators. Furthermore, the Histology core will allow junior investigators to access the equipment and technical expertise to prepare samples for a wide variety of high resolution imaging techniques. The Core Director and technical staff will provide all project investigators and their students/staff assistance in experimental design, sample preparations for specific types of morphological analyses, and selection of the appropriate levels of imaging resolution. Additionally, the core will provide investigators and their trainees with comprehensive training in a wide variety of sample preparation techniques and analysis across a spectrum of tissue-specific applications. To maximize the impact of the NIH investment in biomedical research within North Dakota, the Histology Core Facility will provide access and support to other investigators, within the UND SMHS UND researchers who are not part of the medical school, and researchers from other North Dakota universities such as North Dakota State University, tribal colleges through INBRE, and other research institutions such as USDA-Grand Forks Human Nutrition Research Center; however, a fee-for-service approach will be applied to investigators outside this COBRE, and these fees will help to sustain this center.

Human respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory disease in infants and young children worldwide. The global mortality rate due to RSV among infants and young children is between 66,000 and 234,000 per year. Currently, there is no licensed RSV vaccine or specific antiviral therapy available. Although a variety of approaches have been taken to develop a vaccine, host-pathogen interaction approach to identify effective countermeasures is currently underdeveloped. A genome-wide siRNA screen identified actin-related protein 2 (ARP2) as a host factor for RSV infection. RSV infection induced filopodia and increased cell migration in the respiratory epithelial cells. Filopodia are appeared to be a novel mechanism of cell-associated RSV spread. ARP2 contributes to filopodia-driven RSV cell-to-cell spread. The overall objective of this proposed research is to determine how RSV modulates the host cytoskeleton signaling in filopodia-driven cell-to-cell spread. Three specific aims are proposed to examine the central hypothesis is that RSV infection hijacks cytoskeleton signaling involved in actin polymerization and exploits it to facilitate cell-to-cell spread through filopodia. Aim 1, Delineate Rho GTPases cell signaling involved in RSV-driven filopodia induction for cell-to-cell spread; Aim 2, Identify cellular and viral factors for the filopodia-driven RSV spread; and Aim 3, Determine integrin signaling is an upstream regulator of the filopodia-driven RSV spread. This study will contribute significantly toward the understanding of a novel RSV spread mechanism. Additionally, they will lay the foundation for the identification of therapeutic targets to combat RSV infection.

Summary The Histology Core at UND was established to improve the infrastructure supporting our successful implementation of the Phase 1 Center for Excellence in Host Pathogen Interactions COBRE at the University of North Dakota School of Medicine and Health Sciences. The Core was developed to provide high quality instrumentation, tissue preparation, staining, image analysis services, and training in a wide spectrum of fundamental and advanced histological techniques to COBRE research investigators. The Core also provides access and support to non-COBRE investigators within and outside the UND SMHS, as well as those from institutions adjoining (USDA-Grand Forks Human Nutrition Research Center) and in neighboring cities (North Dakota State University, North Dakota primarily undergraduate institutions and tribal colleges). The Core remains essential for successful growth of the host pathogen interaction enterprise at UND and completing al four of the projects proposed in this Phase 2 renewal application. The Core evolved from being a primarily shared equipment facility with provided user training to now a complete drop off service facility for users across the UND campus. Multiple tissue sectioning and staining services coupled with whole slide brightfield or fluorescent imaging and image quantitation have made the Core invaluable to growth of the research enterprise at UND. In Phase 2, the Core will continue to assist COBRE team members and the broader UND/ND research community with experimental design specifically with regards to application-specific sample preparation techniques, identifying appropriate analytical tools available, resolution restrictions, and quantitative morphological techniques. The Core will also provide service, training, and instruction to COBRE and other users in all aspects of instrument use, safety, tissue sample preparation, and aid with trouble shooting all aspects of tissue preparation and analysis. Finally, the Core will implement a business plan that includes strategies to continue expanding the user base and provide fee-for-service assistance in all aspects of histo- and immunochemical detection methods and analyses, thus paving a way to long-term sustainability of the Core.

Summary This COBRE Phase 2 application proposes continued support of the UND Center for Excellence in Host- Pathogen interaction (HPI). The long-term goal of this center is to develop a deeper understanding of host responses to viral, bacterial and parasitic insults leading to acute and chronic inflammatory diseases. The vision of this Center is to continue to inspire interest in the study of host-microbe interaction and perform paradigm- shifting science that supports the notion that disease development is an interplay of the interaction between a susceptible host, foreign insult and conducive microenvironment. In Phase 1 this center made significant progress by expanding the number of investigators studying various aspects of infectious and inflammatory diseases (from the initial group of 9 labs to now 18 labs). Since the funding of Phase 1 in 2016, this core group of COBRE investigators has made significant contributions to the field by producing 169 publications, $23,617,386 in extramural funding, and 74 speaking engagements (local, national and international). With the project leader graduation success rate of 80% (4 out 6 investigators graduated with R01 funding) in Phase 1, this Center will continue to promote research on host-microbe interaction by: 1) bringing together four young investigators working cohesively in an integrative, collaborative, and multidisciplinary manner on research encompassing extremely timely COVID-19 infection, intestinal dysbiosis in food allergy, gastrointestinal parasitic infection, and viral interaction with respiratory epithelium; 2) enhance the innovative research capabilities of the Center by supporting 3 existing Phase 1 Core facilities; 3) establishing a new Computational Data Analysis Core to meet the emerging requirements of COBRE investigators; and 4) attract new investigators to the group by supporting pilot grant mechanisms. The ultimate goal is to transition the HPI COBRE to a sustainable, well- organized academic center which will serve as a conduit for increased interaction between investigators from diverse backgrounds with a thematic interest in pursuing research on various aspects of host-microbe interactions.

Summary Although Alzheimer?s disease (AD) is an age-associated neurodegenerative disease, continuing evidence demonstrates pathophysiology outside of the brain. This suggests a more complex process of disease with systemic manifestations as well. Numerous studies now demonstrate that changes in the oral cavity have a relationship with AD. Human patients have elevated salivary A? concentrations and reported problems with saliva flow. In addition, periodontal disease, tooth loss, and overall poor oral health are all positive risk factors for AD. This suggests that AD and periodontal health may have a reciprocal relationship. Using two different transgenic mouse amyloidosis models of AD, APP/PS1 and AppNL-G-F mice, we verified not only A? secretion in saliva, but a unique disease-associated oral microbiome and enamel thinning and increased cavities compared to wild type controls. Based upon these findings and prior work by others, we hypothesize that that oral cavity changes are a peripheral manifestation of AD contributing to disease progression. We will continue using the AppNL-G-F mouse line to fully define oral health across age and disease stage in the first aim. In the second aim we will determine whether salivary secretion of A? is needed for the oral dysbiosis and decline in oral health in the AD line. In the third aim we will determine whether the oral dysbiosis is specifically responsible for the decline in oral health and brain presentation of disease in the mice. This study will define an innovative mechanism demonstrating that oral cavity dysbiosis and dysfunction is a characteristic of disease which also contributes to AD progression. We expect to find that salivary A? secretion contributes to oral dysbiosis and changing the oral microbiome is sufficient to ameliorate disease presentation in the brain. This will demonstrate a new bi-directional understanding of disease involving a mouth-brain axis.

Summary The goal of Administrative Core in Phase 2 is to continue centralizing and managing resources necessary to enhance the success of the COBRE on Host-pathogen Interactions (HPI). Building on the success of Phase 1, this Core will provide support to investigators focused on determining the mechanisms underlying immune modulations in the host upon interaction with various microbes to identify possible treatments for devastating inflammatory diseases. Specifically, the concerted effort will focus on (1) expanding the research enterprise of this center by supporting and recruiting junior investigators working on host-microbe interactions that are central to human health and diseases; (2) facilitating productive scientific interactions by organizing networking opportunities through annual symposium and seminar series ; (3) providing an individualized and tailored mentoring program for each investigator; 4) providing oversight and support for mentoring programs through Internal and External Advisory Committees with regular meetings; 5) raising the national profile of the group by providing cutting edge infrastructural support; 6) establishing a new Computational Data Analysis Core facility to provide cutting-edge bioinformatics analytical and interpretative support for the group; 6) providing administrative support to the existing Cores (Histology, Imaging and Flow Cytometry; and 7) fostering collaboration between the other North Dakota COBRE, INBRE and CTR DaCCoTA grant supported groups and between individuals in the respective groups. Successful completion of these goals in Phase 2 of our COBRE will elevate this center to a nationally recognized level with a group dedicated to understanding various aspects of host-microbe interactions in human health and disease. With the recent funding of a Phase 2 Epigenetics COBRE and a Phase I Clinical Translational Research Center DaCCoTA, our HPI COBRE Phase 2 has an unprecedented opportunity at hand to execute high-quality, cutting edge research of immense therapeutic and clinical potential.