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Collaborative Research Grants (IUCRG) — 2013-14 Recipients

Examining Settlement, Environmental, and Agricultural Histories Over the Past 2,000 Years Across the Midcontinent of North America”: Broxton W. Bird (Department of Earth Sciences, School of Science, IUPUI), Jeremy J. Wilson (Department of Anthropology, School of Liberal Arts, IUPUI)

Bird, Wilson, and research team members from IUPUI and IU-Bloomington will examine the relationship between climate change, human impacts to the environment, and settlement histories over the past 2,000 years in the Midwestern United States. Sediment cores will be extracted from a series of lakes in Indiana and Illinois and paired with the existing archaeological records from Native American population centers in order to explore the connections between subsistence practices, cultural change, and climatological factors. The field and subsequent laboratory investigations will enable the research team to quantify the human signatures, such as soil nutrient status and increased sedimentation resulting from agriculture, and disentangle them from the natural conditions including temperature and hydroclimate variability. This research will shed light on the pressures shaping human societies through time, the intentional and unintentional impacts of early horticultural and agricultural societies, and place modern human impacts into a long-term context that is critical to understanding the continued warming and instability currently being experienced in the breadbasket of American grain production. Few comprehensive climate and landscape history models exist for the Midwest, rendering this project that assembles archaeologists, geologists, geochemists, climate modelers and paleoecologists relatively unique. The research will also involve nationally recruited undergraduates from groups traditionally underrepresented in the sciences as part of Wilson and Dr. G. William Monaghan’s (Indiana Geological Survey) Angel Mounds National Science Foundation Research Experiences for Undergraduates program.

Preclinical Studies: Use of TRPV4 Antagonists to Treat Hydrocephalus: Bonnie Blazer-Yost (Department of Biology, School of Science, IUPUI), Feng Zhou (Department of Anatomy and Cell Biology, IU School of Medicine), Daniel Fulkerson (Department of Neurological Surgery, IU School of Medicine), Paul Territo (Department of Radiology and Imaging Sciences, IU School of Medicine)

Hydrocephalus or “flood water in the brain” is a serious and often deadly disease that can arise from injury, infection or other causes. The increased pressure can cause lasting damage to brain tissue and irreversible developmental problems are not uncommon. Unfortunately, there are currently no drugs available to treat hydrocephalus and the only way to help newborns and children with this condition is to surgically implant shunts to drain the fluid into another part of the body. Shunts are prone to failure and infection. In an animal model of hydrocephalus, Blazer-Yost and Gattone serendipitously found that a drug being developed for treating fluid build-up in the lung may also be effective in the treatment of hydrocephalus. The IUCRG proposes studies that will build on this novel finding. In addition to the initial investigators, a collaborative team has been assembled to bring individuals with various expertise together to optimize the possibility of transitioning the initial observation into proof of principle pre- clinical studies. The senior people added to the team include Zhou, a well respected developmental neurobiologist, Fulkerson, a pediatric neurosurgeon who specializes in hydrocephalus and Territo, an imaging expert who specializes in developing state-of-the-art techniques to monitor the development of pathologies such as hydrocephalus. The ultimate goal of this research is to determine if a new drug, known as a TRPV4 antagonist, can be safely and effectively repurposed for the treatment of children with hydrocephalus.

Collaborative Development of in Vivo Microvascular Imaging and Multiscale Computer Simulations to Identify the Mechanisms of Diabetic Vasculopathies and Provide Personalized Predictions of Disease Progression: James Glazier (Department of Physics, College of Arts and Sciences, IUB), Stephen Burns (School of Optometry, IUB), Thomas Gast (School of Optometry, IUB)

Gast, Burns, and Glazier have received a grant from the Office of the Vice President for Research which will allow an extension of retinal imaging work done by Burns and Gast in the Optometry School at IU. This imaging allows the examination of the anatomy of the smallest blood vessels in the human eye, the capillaries of the retina. These capillaries are one of the most vulnerable structures to damage from diabetes. Diabetes makes these vessels either become leaky or become occluded so that the retina either is damaged by proteins and fats leaking from the blood vessels or suffers from a lack of blood entirely; the equivalent of a microstroke. Either of these forms of damage tends to occur preferentially near the center of vision and can even cause blindness. The Indiana University AOSLO, the specialized camera used to make these images, allows the structure and the blood flow in these capillaries to be determined. By imaging specific areas of the diabetic retina over and over at intervals of several months, the progression and pattern of the development of this vascular disease will be determined. This data will then be interpreted through models of the retinal anatomy and physiology developed by Dr. Glazier’s laboratory in Biocomplexity. This modeling will allow prediction of the course of retinal damage over time. It is hoped this will allow both a better understanding of this common as well as serious condition, and will allow improvements in treatment in the future.

Human Hair and Nail Analyses as Non-Invasive Biomarkers of Exposure to Brominated and Organophosphate Flame Retardants: Ronald Hites (School of Public and Environmental Affairs, IUB), Ka He (School of Public Health, IUB), Amina Salamova (School of Public and Environmental Affairs, IUB)

A biomarker is a measurable characteristic that can be used as an indicator of a particular disease state or some other physiological state of an organism. Human biomarkers can include blood or other tissues, which are analyzed quantitatively for a specified pollutant or family of pollutants to give an indication of the level of contamination in human body. Unfortunately, obtaining human biomarker samples can often be problematic. Many people are not willing to donate blood or tissue samples; this is especially true for children. Thus, establishing non-invasive biomarkers is essential in human biomonitoring. Hair and nails have been used for detecting heavy metals and drugs in humans for decades, but their use for persistent organic chemicals, such as flame retardants, remains limited. Flame retardants are organic chemicals that are added to a wide variety of consumer and industrial products, such as plastics, electronic equipment, furniture, textiles, and building materials to delay ignition and slow the spread of fire. Brominated and organophosphate flame retardants are among the most widely used organic flame retardants currently in production. Exposure to flame retardants is associated with a number of toxicological effects, including endocrine disruption, mutagenicity, carcinogenicity, reproductive toxicity, neurotoxicity, learning disabilities, and obesity. This project brings together two groups of researchers collaborating to develop non-invasive human biomarkers, such as hair and nails, for assessing human exposure to flame retardants.

MicroRNA Regulates Vascular Calcification Progression in Chronic Kidney Disease: Sarath Janga (School of Informatics and Computing, IUPUI), Sharon Moe (Department of Medicine (Nephrology, IU School of Medicine), Neal Chen (Department of Medicine (Nephrology, IU School of Medicine)

Vascular (arterial) calcification is a prominent finding in aging, diabetes, chronic kidney disease (CKD), and inflammatory diseases, and is associated with increased morbidity and mortality. Risk factors include previous calcification, disordered mineral metabolism (e.g. hyperphosphatemia), diabetes, older age, and duration of CKD/dialysis. The greatest risk factor for progression is the magnitude of existing arterial calcification. However, the mechanism of such propagation is unknown, and data suggest it is far more complex than physicochemical changes in mineral concentrations. The goal of the proposed study is to test the hypothesis that calcified vascular smooth muscle cells from CKD animals promote arterial calcification by the transfer of pro-mineralization microRNA to adjacent cells through matrix vesicles. This represents a multidisciplinary collaboration involving the investigators working together to try to understand the role of microRNA as a mediator of vascular calcification via the transfer of microRNA to adjacent cells, testing the hypothesis that this leads to propagation of arterial calcification. The investigators are studying the pathogenesis of vascular calcification in kidney disease. However, the studies are also applicable to aging, diabetes and other diseases. In certain diseased states, most notably cancer, microRNAs have been known to be key regulators of pathogenic processes and are important mediators. Therefore, the measurement of microRNA in blood also offers the potential for a novel biomarker of individuals at risk of progression of vascular calcification as a framework to study a variety of diseases by differentiating calcifying and non- calcifying exosomes.

The Identity and Role of Hub Neurons in Local Cortical Networks: Xaioming Jin (Department of Anatomy and Cell Biology, IU School of Medicine), John Beggs (Department of Physics, College of Arts and Sciences, IUB)

The human brain depends on networks of billions of highly interconnected neurons. The pattern of information flow in such networks is poorly understood and cannot be inferred from studying anatomy alone. Recently, John Beggs’ lab found that information flow in the cerebral cortex was distributed in a very uneven manner, with some neurons (“hub neurons”) participating in far more information flow than expected by chance. This was evident in the distribution of information flow strengths, the distribution of total information flow into and out of each neuron, and in the distribution of connections with significant information flow per neuron. This small proportion of hub neurons (~5%) may play a key role in normal functions and in diseases. In this collaborative research project, Beggs' and Jin’s labs will use functional imaging and electrophysiological recording techniques to study neuronal activity in cultured brain tissue and in brain of live animals, and assess information flow in hundreds of neurons recorded simultaneously in these experiments. Specifically, the goals of this pilot project include determining the stability of hub neurons over time in culture brain slices, characterizing their electrophysiological and morphological properties, and detecting hub neurons in the cerebral cortex in mice. Understanding the structure and function of hub neurons may help us to interpret how local cortical networks function and potentially allow us to target hub neurons for controlling certain neurological diseases such as epilepsy.

Structural/Functional Mechanisms of Action of GroEL/ES (HSP60/10) Inhibitors: Steven Johnson (Department of Biochemistry and Molecular Biology, IU School of Medicine), Lingling Chen (Department of Biology, College of Arts and Sciences, IUB)

For the past seven decades, a plethora of therapeutics has been available for combatting infectious diseases. However, prolonged antibiotic use and misuse has led to the emergence of drug resistance, to the point where limited or no therapeutic options remain for once easily treatable pathogens. To counteract the growing superbug threat and avert regressing towards a pre-antibiotic era, the identification of mechanistically unique antimicrobials is essential. Towards this goal, we are developing a new class antimicrobials that target a unique protein complex called the GroEL/ES chaperonin system. This biological machine assists the proper folding and functioning of a myriad of cellular proteins. Experimental evidence demonstrates that inactivation of GroEL/ES is detrimental to cell survival and thus, targeting of this molecular machine represents a promising antibiotic strategy. Because these inhibitors block a previously unexploited biochemical pathway, they retain efficacy against superbugs such as methicillin resistant Staphylococcus aureus (MRSA). Since this chaperonin system is found in all organisms, these antibiotics hold promise for application against a broad spectrum of infectious diseases. Human cells have a similar chaperonin, termed HSP60/10, which we are additionally studying as a therapeutic target for certain cancers and neurodegenerative diseases for which HSP60/10 misregulation and malfunction are associated. Using X-ray crystallography and other biophysical/biochemical methodologies, our present studies seek to understand how our inhibitors alter the mechanics of these chaperonin systems. With a clearer picture of their function, we will be better positioned to optimize the efficacy of these drug candidates as antimicrobial, anti-cancer, and neurodegeneration therapeutics.

Building Statistical Language Processing Algorithms for Automated Coding of Semi-Structured Interview Data in Clinical Schizophrenia: Michael Jones (Department of Psychological and Brain Sciences, College of Arts and Sciences, IUB), Paul Lysaker (Department of Psychiatry, IU School of Medicine), Tim Rubin (Department of Psychological and Brain Sciences, College of Arts and Sciences, IUB)

Schizophrenia is a devastating mental illness that affects approximately 1% of the U.S. population over the age of 18, and incurs approximately 62 billion dollars in health care costs per year. Identifying schizophrenia and categorizing individual patient’s symptoms is critical to proper treatment, but is a slow and expensive process requiring highly trained clinicians. We propose the use of statistical learning and classification methods to increase the speed, efficiency, and reliability of patient identification and categorization. Using semi-structured linguistic data generated by both schizophrenia and control patients, we will use unsupervised learning algorithms to identify latent semantic dimensions that are characteristic of various behavioral symptoms associated with different types of schizophrenia. In addition to employing unsupervised algorithms to learn features associated with symptoms of schizophrenia, we will use novel algorithms that are designed specifically to measure the semantic coherence of linguistic data at varying degrees of granularity (a critical feature for identifying schizophrenia or other thought-disorders in patients). Using both topic-based features and coherence- measures as inputs, we will then evaluate numerous state-of-the-art machine learning classifiers, in order to develop algorithms which can (1) automatically classify subject data as schizophrenia or control, and (2) automatically assign finer-grained behavioral symptoms (such as positive-delusions or semantic-coherence). These tools could have a profound impact on public health, both in terms of identifying schizophrenic patients and as an aid in treatment of those patients by identifying the specific symptomatic characteristics of individual patients.

Hemoglobin Expression and Function in the Retinal Pigment Epithelium: Brian Kennedy (Department of Cellular and Integrative Physiology, School of Medicine, IU Northwest), Nancy Mangini (Department of Anatomy and Cell Biology, School of Medicine, IU Northwest), Gabi Waite (Department of Cellular and Integrative Physiology, School of Medicine, Terre Haute), Harold Olivey (Department of Biology, School of Science, IU Northwest)

The retinal pigment epithelium (RPE) is a continuous sheet of epithelial cells that lies between the retinal photoreceptors and their primary blood supply. Due to its location, the RPE provides critical support functions that sustain photoreceptor viability. Recent work indicates that the oxygen binding protein hemoglobin is expressed in several tissues besides red blood cells. In particular, hemoglobin has been shown to be expressed in the RPE, where it is one of that cell’s most abundant proteins. To date the function of hemoglobin in the RPE has yet to be established. In analogy with other cell systems, hemoglobin in the RPE could serve a protective function. One candidate function would be oxygen buffering, which could guard against retinal hypoxia. Since hemoglobin can act to scavenge reactive oxygen species, it could also function to protect the RPE against oxidative damage. These potential functions have direct clinical relevance since both retinal hypoxia and oxidative stress are implicated in ocular pathologies, such as macular degeneration and diabetic retinopathy. The present proposal will describe hemoglobin expression in cultured human RPE cells as well as in the chicken embryo during eye development. Additionally, the project will employ an enzymatic system that precisely controls oxygen and hydrogen peroxide levels to examine hemoglobin function in cultured RPE. Hemoglobin in RPE is envisioned as a potential therapeutic target that could be manipulated in an effort to protect against age- related visual pathology.

Platelet Activating Factor Receptor as a Prophylactic Target for ATLS Leading to SIRS/MODS: Raymond Konger (Department of Pathology and Laboratory Medicine, IU School of Medicine), Jeffrey Travers (Department of Dermatology, IU School of Medicine), Attaya Suvannasankha (Department of Medicine (Hematology), IU School of Medicine)

Acute tumor lysis syndrome (ATLS) is the most common fatal oncologic emergency. ATLS resulting in severe organ damage occurs in approximately 5% of all hematologic malignancies. ATLS occurs as a side effect of effective anti-cancer treatment. Due to rapid advances in anti-cancer treatments, the frequency of ATLS is increasing. Currently, it is believed that ATLS results from the release of intracellular contents from dying cells that cause disturbances in kidney function and abnormal heart beats. For unknown reasons, some individuals also progress to tissue damage in multiple organs. We propose that ATLS can lead to a shock-like syndrome called systemic inflammatory response syndrome (SIRS) that is seen with other types of tissue cell death, such as burns and infection. We have shown that a compound called platelet activating factor (PAF) is produced by tumor cells treated with radiation and chemotherapy. PAF is also known to promote the development of shock. Thus, we propose that PAF may be responsible for severe ATLS. The use of drugs which block PAF are effective in treating shock syndromes if they are given early. To examine our hypotheses, we will develop two different animal models of ATLS to determine if ATLS does lead to shock. We will then determine whether strategies that block PAF also suppress ATLS- induced SIRS. Finally, we will determine if PAF is produced upon initiation of treatment in human volunteers at high risk of ATLS. Hopefully, this could lead to human studies to determine if PAF blockade prevents ATLS-induced organ failure.

Three-Dimensional In Vitro Culture Model for Functional Liver Tissue Engineering: Chien-Chi Lin (Department of Biomedical Engineering, School of Engineering and Technology, IUPUI), Guoli Dai (Department of Biology, School of Science, IUPUI)

The liver is a vital organ for detoxification, protein synthesis, and secretion of digestive enzymes. These liver functions are accomplished by hepatocytes, the major cell type in the liver. Therefore, significant research efforts have been dedicated to the understanding of hepatocyte physiology and pathophysiology, as well as to the prevention and treatment of liver diseases such as viral hepatitis and liver cancers. However, many of these studies rely on culturing isolated hepatocytes in petri dishes, which are flat and rigid surfaces that do not resemble native liver microenvironment. As a result, most of the isolated primary or immortalized hepatocytes lost their natural functions when cultured on conventional two- dimensional (2D) surfaces. To address this issue, we propose to establish and optimize novel three- dimensional (3D) hydrogels with highly defined biophysical and biochemical properties for in vitro hepatocyte culture. This novel 3D culture system will serve as a platform for mechanistic understanding of hepatocyte growth and function. Furthermore, we will adapt this culture system to the development of first in vitro 3D hepatitis B virus (HBV) infection model. Critically, our 3D hydrogels significantly enhanced the expression of some liver detoxification genes and the receptor for HBV entry. The support from this IUCRG award will foster the newly established collaboration between the School of Engineering & Technology (Lin) and School of Science (Dai) at IUPUI. Our novel hydrogel hepatocyte culture system also holds the potential in new drug development to assist those who suffer from acute and chronic liver diseases.

An Experimental Investigation of the Contexts and Mechanisms Shaping the ProceduralPreferences of Judges, Attorneys, and the Public When Triaging Family Law Disputes: Victor Quintanilla (Maurer School of Law, IUB), Mary Murphy (Department of Psychological and Brain Sciences, College of Arts and Sciences, IUB)

Our civil justice system fails to meet the needs of millions of indigent and middle-income Americans, even when fundamental legal issues about families, such as divorce and child custody, are at stake. Each year, a rising tide of Americans proceeds pro se (without counsel) in family law cases. At the same time, an increasing number of family law cases, counseled and pro se alike, are channeled out of the formal legal system and triaged into mandatory alternative dispute resolution (ADR). Yet there is a dearth of experimental research examining when judges, lawyers, and the public prefer to triage family law cases to ADR (e.g. mediation) instead of formal legal procedures, and why? Drawing on social psychological and experimental methods, and advanced statistical analyses, this project will explore 1) the degree to which common features of family law disputes causally shape stakeholders’ procedural preferences, and 2) the causal mechanisms behind why these contextual variables affect procedural preferences. Broader impacts of the research include that this interdisciplinary team will be the first to harness and connect two new, exciting methods for performing socio-legal inquiry by experimentally manipulating realistic films of initial courtroom hearings and by conducting advanced statistical tests of moderated mediation. Moreover, the research will reveal similarities and differences across stakeholder preferences, and distinguish between affective and cognitive psychological mechanisms. In short, the findings will allow judges, attorneys, and the public to better understand, empathize, and work with one another to promote the fairness and legitimacy of family law procedures.

Obesity and Host Immunity to Influenza Virus Infection: Jie Sun (Department of Pediatrics, IU School of Medicine), Carmella Evans-Molina (Department of Medicine (Endocrinology, IU School of Medicine)

Obesity is a global public health concern and it is now estimated that close to one-third of the adult population in the United States are clinically obese. In addition to well-established associations with metabolic disorders like type 2 diabetes mellitus (T2DM) and cardiovascular disease, obesity also increases the host susceptibility to a variety of pathogens, including influenza virus. For instance, during the 2009 H1N1 influenza pandemic, obesity was convincingly identified as an important risk factor for multiple markers of disease severity, including hospitalization, intensive care unit admission and death following infection. At present, the underlying mechanisms associated with the increased susceptibility to influenza virus infection in obese hosts remain poorly understood. Based on recent findings from the Sun and Evans-Molina lab, we believe that defective expression and/or function of macrophage PPAR-D, a nuclear protein that modulates metabolic functions, underlie enhanced host susceptibility to influenza virus infection in obese individuals. We propose here to fully test this hypothesis and repurpose a diabetes drug to activate and/or restore PPAR-D function as a potential therapeutic to reduce influenza virus infection and complications in obese individuals. We believe our application will shed light on the mechanisms of influenza pathogenesis and open the door to new therapeutic modalities to protect against influenza infection and its complications in settings of obesity and metabolic disease.

Ossabaw Swine as a Novel Platform for Analyses of Anti-Diabetic Agents on Islet Function: Debbie Thurmond (Department of Pediatrics (Endocrinology, IU School of Medicine), Johnathan Tune (Cellular and Integrative Physiology, IU School of Medicine)

Type 2 diabetes (T2D) affects >8% of U.S. adults. If current trends continue, 1 in 3 children born after 2000 will develop diabetes in their lifetime. T2D results when beta cells in the pancreas fail and die. A central question in the field relates to how and when beta cells malfunction over the course of pre- diabetes to overt development of T2D. To address this critical issue, studies in this proposal will utilize the obese Ossabaw swine model of pre-diabetes, which is located only here at IU. Integrative experiments will utilize this clinically relevant model to interrogate new molecular mechanisms and remediation strategies to halt the development and/or progression of pre-diabetes to T2D from the perspective of beta cell function and survival.

The Drought Effects on Forest Carbon Uptake and Water Use-Coupling Stable Isotopes, Eddy Covariance and Process-Based Modeling: Lixin Wang (Department of Earth Sciences, School of Science, IUPUI), Kim Novick (School of Public and Environmental Affairs, IUB)

The magnitude of forest carbon uptake depends strongly on meteorological conditions. How drought affects forest carbon uptake is largely unknown and this knowledge gap significantly hinders our prediction of carbon sequestration by forest ecosystems. By taking advantage of a long-term dataset of forest evapotranspiration and carbon uptake in the Morgan-Monroe State Forest of Indiana, and by coupling that data with state-of-the-art laser-based stable isotope techniques and process-based modeling, we will test the hypothesis that variations in temporal and spatial vegetation water use regulate drought effects on ecosystem-level carbon dynamics. The results from this work will have important implications in predicting the forest response to future environmental changes.