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Collaborative Research Grants (IUCRG) — 2011-12 Recipients

"A Search for New Spin-Dependent Forces of Nature;" William Snow (College of Arts and Sciences), Joshua Long (College of Arts and Sciences), Ricardo Decca (School of Science), Alan Kostelecky (College of Arts and Sciences) and Ruihu Cheng (School of Science)

The possible existence of new weak forces of nature with ranges of macroscopic scale (nanometers to millimeters) is attracting increased scientific attention. Such possible forces are playing an increasingly important role in many theoretical speculations in physics connected with the mysterious dark matter and dark energy of the universe, but are still poorly constrained by existing experiments. We propose to conduct sensitive experimental searches for possible new forces over these ranges that couple to the spin of neutrons and electrons. "Spin" is a property of particles analogous to the spin of a rotating basketball, formally representing the angular momentum of a particle at rest. Mass and spin are the most fundamental properties of particles in spacetime: protons, neutrons, and electrons all have spin as well as mass. We propose to create different forms of spin-aligned (that is, polarized) matter consisting of neutrons and electrons, and search for possible new interactions with other unpolarized objects in experiments which can be many orders of magnitude more sensitive than past work. This work is similar in spirit to the attempts to create and study new particles at the Large Hadron Collider but very different in scale: these "tabletop" experiments can sense very weakly interacting light particles to which the LHC is insensitive.

An IUB/IUPUI collaboration will conduct work in both theory and experiment relevant to this search for possible new spin-dependent forces. Separate efforts at IUB and IUPUI in the past have already conducted some of the most sensitive experiments to search for possible new spin-independent forces. We will investigate how much unwanted effects from the magnetic fields made by polarized objects can be suppressed (and therefore how sensitive the proposed experiments at IUB and IUPUI will be to new spin-dependent forces). We will also investigate the implications of these measurements for a general theory which parametrizes possible deviations from Einstein's theories called the "Standard-Model Extension", which has been developed at IUB over the last several years. Constraints on spacetime "torsion", the distortion of spacetime by spin allowed in Einstein's theory of gravity, are of particular interest. "Amyloid Precursor Protein Brain Neuronal Markers in Children with Autism;" Deborah Sokol (School of Medicine). Debomoy Lahiri (School of Medicine), Dean Hawley (School of Medicine) and George Sandusky (School of Medicine)

Our aim is to establish a collection of normal pediatric brain samples to be used for research purposes through the collaboration of three IUPUI Departments (Neurology, Psychiatry, and Pathology). We will collaborate on acquiring pediatric brains from deceased patients at Riley to be used for research purposes including our ongoing autism research. We have joined efforts with the Autism Tissue Program (ATP), a national organization dedicated to collecting brain specimens. This collaborative project, with extension to the national level, should increase Indiana University’s research competitiveness and reputation, thus fulfilling the purpose of the IUCRG-RPF within the category of "Biological, Physical and Health Sciences". Specifically, this project will enable the further study of amyloid precursor protein (APP) brain biomarkers in children with autism and fragile X syndrome (FXS), a genetic neurodevelopmental condition associated with autism. A biomarker is a protein measured in blood or tissue whose concentration reflects the severity or presence of disease. Drs. Sokol and Lahiri have preliminary evidence suggesting high levels of APP in blood and in a few samples of brain tissue from children with severe autism and FXS. They will determine these markers in a larger sample of brain tissue obtained from this study and from samples provided from ATP, which is a critical next step in their research. It is hoped that the APP brain biomarker project will demonstrate the importance of establishing a pediatric brain tissue collection at IUPUI and enable future research into pediatric neurological conditions such as epilepsy, brain tumors and stroke.

"Bacterial Vaginosis (BV) and Sexually Transmitted Infections (STI) among Women who have Sex with Women and Men (WSWM) and their Sexual Networks;" Vanessa Schick (School of Health, Physical Education and Recreation), James Fortenberry (School of Medicine), David Nelson (College of Arts and Sciences), Barbara Van Der Pohl (School of Health, Physical Education and Recreation)

Bacterial vaginosis (BV) is associated with many negative health conditions for women. Scientists and physicians have thought for many years that BV was sexually transmitted but this has never been proven. This proof is important for development of more effective approaches to BV treatment and prevention. Recent technologic innovations in bacterial DNA sequencing have made it possible to confirm the transmission of BV from one partner to another by matching bacterial DNA sequences in the two partners. Thus, the confirmation of sexual transmission requires research where information and samples are obtained from both members of a sexual partnership.

Women who have sex with men and women (WSWM) and their partners are the ideal population for study because BV and other STI are very common among these women. In the proposed study, 75 WSWM will be invited to participate in a longitudinal diary study on their sexual health/behaviors. During this time, they will also be asked to provide regular self-collected oral, vaginal and anal specimens. In addition, participants will be asked to recruit sexual partners up to an aggregated total of 150 partners. Participants’ partners will also provide detailed sexual event data and corresponding self-collected samples. The samples will be tested using sophisticated bacterial DNA sequencing tools, and this information will be combined with detailed sexual behavior information to look for proof of sexual transmission of bacteria associated with BV.

"Balance Control in Patients with Age-Related Macular Degeneration;" Shirin Hassan (School of Optometry) and John Shea (School of Health, Physical Education and Recreation)

The aim of this study is to understand how people with age-related macular degeneration (AMD) maintain their balance while standing. AMD is the leading cause of untreatable visual impairment in adults 65 years and older. Poor balance, the risk of falling and falls are significant health concerns for older adults and visual impairment is a risk factor for falls. We will test the balance control of 25 participants with AMD and 25 participants with normal vision under eight sensory conditions. Our research will determine how vision loss affects balance control, and whether people with AMD can rely on the vestibular system of the ear, stretch receptors in the limbs, touch receptors in the feet and on vision to maintain balance control. We will also determine how much vision must be lost before balance is impaired. The results of this study will provide medical doctors, optometrists and physical therapists with evidence-based guidelines of when to refer an AMD patient for balance training. Our findings will also be of value to health care professionals who design rehabilitative strategies to improve balance control in patients with visual impairment.

"Effects of Chronic Cannabis Abuse on Associative Learning and Neuroplasticity in Early Adolescence and Young Adults;" Amanda Bolbecker (College of Arts and Sciences), Kenneth Mackie (College of Arts and Sciences), William Hetrick (College of Arts and Sciences), Charles Goodlett (School of Medicine) and Alan Breier (School of Medicine)

Marijuana (Cannabis sativa) is one of the most widely abused drugs in the U.S., and long-term use is associated with cognitive difficulties. Cannabis use during adolescence also increases the risk of schizophrenia. Both the acute consciousness-altering effects and the long-term harmful effects of cannabis are believed to result from the actions of one component of cannabis, tetrahydrocannabinol (THC), on brain cannabinoid receptors. Great interest has been generated recently in a non-psychoactive constituent of cannabis, cannabidiol, because it appears to protect against THC’s harmful effects. The cerebellum is a brain region that is particularly sensitive to THC because it has high concentrations of cannabinoid receptors. We recently showed that a basic form of learning that depends critically on the cerebellum, eyeblink classical conditioning, is impaired in college students who are chronic cannabis users.<

This adverse effect of chronic cannabis use provides a unique opportunity to use an animal model to study how chronic exposure to THC during adolescence impairs cerebellar function, and to determine the potential protective effects of cannabidiol. This project will test the hypothesis that long-term THC exposure in adolescent rats will impair eyeblink conditioning. In addition, we predict that deficits that emerge with THC exposure alone will be prevented in animals simultaneously receiving THC and cannabidiol. We also will evaluate the effects of long-term exposure to THC and cannabidiol on the quantity and distribution of cannabinoid receptors in the cerebellum, which will provide critical information about the changes in the brain that underlie any observed behavioral effects.

"Family Environment and Its Role in Outcomes in School-Age Children with Hearing Loss;" Rachael Holt (College of Arts and Sciences), William Kronenberger (School of Medicine), Jessica Beer (School of Medicine) and David Pisoni (College of Arts and Sciences)

Despite progress in the early identification of hearing loss through universal newborn hearing screening and great advancements in hearing health technology, there is still enormous unexplained variability in developmental outcomes in children with hearing loss who receive hearing aids and/or cochlear implants. Although several sources of explanation have been virtually ignored, one source that has been seriously neglected in this population is the child’s family environment. This research will address a significant gap in our understanding of the family environment’s impact on critical developmental domains in children with hearing loss by achieving two goals: to examine and compare family environment, parent-child relationships, and psychosocial, cognitive and language development of children with hearing loss who use hearing aids or cochlear implants and normally hearing peers; and to identify family factors that enhance or hinder psychosocial, cognitive and language development in children with hearing loss. To address these aims, 30 school-age children will be administered standardized tests of language and cognition. Parents will complete a family environment questionnaire and parents and teachers will complete a child behavior and academic competence questionnaire. Finally, we will video record three standard parent-child play interactions to directly observe family dynamics. Because the ways that families interact with one another can be changed with explicit education and therapy, the exciting promise of this work is the direct impact it can have on the field and on families of children with hearing loss through the development of more targeted and innovative intervention.

"Integrating Clinical Data Systems with Social Context to Map Neighborhood Health;" Lisa Staten (School of Medicine), Christian Mushi (School of Health and Rehabilitation Sciences), Marc Rosenman (School of Medicine) and David Bodenhamer (School of Liberal Arts, Polis Center)

Over the past 30 years, obesity rates and associated diseases such as diabetes have escalated both nationally and locally. Increasingly, neighborhood environments are being examined in relation to residential health. Neighborhoods have both physical and social dimensions, and there are many mechanisms by which both the physical and social characteristics of neighborhoods may influence health. Research indicates that there is potential to modify rates of obesity and associated chronic disease by modifying associated neighborhood factors such as poverty level. While health researchers have long understood that where people live influences their health, new methods are leading to new understandings about the complex relationship between place and health. This project will begin a research initiative to examine the impact of economic development on health in two Indianapolis neighborhoods: the Near Eastside and Near Westside. This study will convene a team from the IU School of Medicine Department of Public Health, IU School of Health and Rehabilitation Sciences, IU School of Liberal Arts (the Polis Center), and the Regenstrief Institute to develop neighborhood-level health indicators from a clinical data system; integrate these indicators with social indicators to create neighborhood snapshots, and; assess the utility of the indicators for neighborhood units. A grant application will use these data to assess health impact of community investment; inform future policy; provide neighborhood specific health data; and develop public health programs.

"Ionizing Radiation Induced DNA Demethylation and Brain Development;" Feng Zhou (School of Medicine), Marc Mendonca (School of Medicine), Yun Liang (School of Medicine), Amy Cristine Lossie (School of Medicine)

There has been an increasing focus on the risks of radiation exposure from medical treatments and escalating industrial use of radiation releasing compounds. Although it is known that X-rays can alter DNA and damage cells in our body, the cause and scope of these changes are unknown, and other potential hazards are unclear. We recently used microCT to detect body structure and demonstrated under the animal setting that there were dramatic changes in DNA methylation, which is a code written on top of DNA that instruct its function. We found that radiation erased the DNA instruction code in brain regions that are important for cognition, memory and emotional processes. It is understood that the DNA instruction code is critical for our gene function and essential in ensuring development and growth from the fetal stage to adulthood, and erasure of this code is harmful. In this project, we will investigate the fundamental questions pertinent to erasure of the DNA instruction code by radiation. The radiation dosage leading to erasure is unclear and the mechanisms for how radiation leads to erasure of DNA methylation are unknown. This project will tease out the effects of radiation dosage and elucidate the key mechanisms of its influence on brain development and its influence by radiation exposure. Upon understanding of these bases, we will design future studies, to understand how radiation as an environmental factor may affect the genes and function of the brain by the erasure of the DNA instruction code.

"MIMP Modeling of Alzheimer's Disease Data Towards A Robust Diagnostic Test;" Jake Chen (School of Informatics), Andrew Saykin (School of Medicine), Xiaogang Wu (School of Informatics), and Li Shen (School of Medicine)

Currently, brain autopsy remain the surest method to confirm Alzheimer’s disease (AD), which is characterized by extracellular plaques of Amyloid β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) of hyper-phosphorylated Tau proteins. Ongoing research studies have actively focused on developing reliable AD biomarkers in patients’ peripheral blood. However, these studies often failed to show consistent accuracy when new samples are tested.

To minimize bias inherent in standard machine learning techniques that rely on training data alone, we propose an innovative technique, multidimensional integrative molecular profile (MIMP) modeling technique. In MIMP models, existing AD-related knowledge, molecular interaction network information, and functional genomics data from other related studies will be integrated together to boost sample classification accuracy and robustness. MIMP modeling particularly can help discover sub-groups of AD-related genes that are previously too weak to detect individually, therefore requiring only a small number of molecular profiling datasets as training sets. Our results will be validated using multiplex proteomic immunoassay data from blood samples collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI).

"Modeling Epithelial Organization;" Robert Bacallao (School of Medicine) and James Glazier (College of Arts and Sciences)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by adult onset development of cysts in the kidney and progressive loss of kidney function. ADPKD is the most common genetic cause of kidney failure and it has been estimated that treatment of ADPKD costs 2 billion dollars per year in U.S. tax dollars. Although genetic mutations that cause this disease have largely been identified, how these mutations actually cause kidney cysts is still not fully understood. Currently no therapeutic options exist to stop disease progression. Normal kidney function depends on cells within the kidney organizing in functional units called tubules. This organization is largely maintained by specialized proteins called cadherins that control how cells organize and maintain large scale structural integrity. Mutations known to cause ADPKD have links to cadherin function. Further, kidney cysts have an additional cadherin, cadherin-8, that is not present in normal kidney tubules. Dr Robert Bacallao’s laboratory has recently discovered that in cells that normally form tubules, just adding cadherin-8 causes them to form cysts. CompuCell3D (CC3D), an open-source computer simulation environment developed in Dr. James Glazier’s lab is used to model a wide range of biological phenomena, including computer simulations of tubule and cyst development. In this project, data from Dr. Bacallao’s cyst formation experiments are coupled to development of Dr. Glazier’s computer models of cyst formation. Computer models then provide a way to test ideas to stop cyst formation. Ultimately, this project has the potential to identify therapeutic interventions to ameliorate the course of ADPKD.

  "Neurobiological Mechanisms Underlying Affect Recognition Deficits After Brain Injury;" Wang Yang (School of Medicine), Dawn Neumann (School of Medicine), Brenna McDonald (School of Medicine), and Arlene Schmid (School of Health and Rehabilitation Sciences)

The ability to recognize how others feel (affect recognition) helps us to acknowledge and respond appropriately to the needs of others. Facial affect recognition is a complex process that relies on multiple processing strategies. Functional neuroimaging studies have been able to link different processing strategies to certain brain structures. Studies show that people with traumatic brain injury (TBI) often have significant affect recognition impairments. Emotion recognition deficits have been associated with inappropriate behaviors, difficulty controlling one’s own emotions, and poor social outcomes. Negative social and emotional behaviors are among the most common and difficult problems to treat after a TBI. There is obviously a significant need to address affect recognition deficits with treatment after TBI. However, it is not fully understood scientifically or clinically why patients with TBI have trouble recognizing emotions from facial expressions. Therefore, in this multidisciplinary pilot project, the investigators will use advanced functional neuroimaging to better understand the underlying causes for these deficits in people with TBI. We will recruit the following 3 groups (10 per group, total =30): 1) TBI with facial affect recognition impairments; 2) TBI without facial affect recognition impairments; and 3) healthy controls. We will compare differences in brain activity and behavioral performance across the three groups during completion of several emotion recognition tasks. By comparing people with and without affect recognition deficits, we will be able to identify which facial affect processing strategies are impaired in people with TBI, which is ultimately crucial for developing effective treatment approaches.

"Novel Anti-cancer Agents Targeting G-Quadruplexes;" Amar Flood (College of Arts and Sciences) and Brittany-Shea Herbert (School of Medicine)

Cancer cells are often said to be immortal. To earn this moniker, it is believed that cancer cells maintain the length of the ends of DNA, the telomeres, to avoid the normal termination of cellular growth when telomeres are too short. . One way they can do this is to over-express an enzyme called telomerase. It recognizes the telomeric ends of the DNA that emerge during cell division and extends them. Fortunately, current theory holds that every once and a while, these ends can also fold up into nicely packaged bundles, called guanine quadruplexes (G-quads), that hide the loose ends, and thus, avoid the action of the telomerase. The long term goal of this proposed work, therefore, is to develop a new class of small drug-like molecules that can stabilize the bundles such that they remain hidden for as long as is necessary to allow the normal cellular life cycle to regain control of the infected cancer cells. To that end, this research will involve three groups of researchers working together to provide proof of principle evidence that a new class of molecular compounds will act in this way. In the Chemistry Department at Indiana University, Bloomington, Flood and his group will synthesize the G-quad-binding compounds and examine how the compounds bind to DNA together with the group at Monash University, Melbourne, Australia. In collaboration with Herbert in Indiana University School of Medicine, they will test the ability of these new compounds to revert cancer cells back to normal.

"Placenta Stem Cell-Based Tissue Engineering Of The Trachea: Airway Management Of The Future;" Stacey Halum (School of Medicine), Michael Murphy (School of Medicine) and Marco Bottino (School of Dentistry)

Life-threatening diseases of the tracheal airway including cancerous and noncancerous growths of the airway, scarring (stenosis), and collapse of the trachea (malacia) affect over 100,000 individuals each year. If the disease process cannot be safely removed surgically, these patients are left without curative treatment options because to date we have no acceptable method of surgically replacing the tracheal airway. Investigations into stem-cell based tracheal airway replacements have been underway in Europe, with initial results quite promising, but their model has relied on culturing the individual patient’s stem cells onto the tracheal implant, which can be too time consuming for most patients with swiftly progressing airway diseases. If a stem cell-based tracheal replacement option could be developed based on universally accepted stem cells, cost could be drastically reduced because large scale production of implants would become feasible. Furthermore, tissue engineered airways could be immediately available for life-threatening cases of airway obstruction due to neoplasm, scarring, collapse or even traumatic injury. Placenta stem cells are an ideal option for creating such a tracheal replacement, because they are attained from tissue that would otherwise be discarded, readily grow into a wide variety of cell types, and are not likely to stimulate an immune (reactive) response when placed into a patient. Therefore, we anticipate that placenta stem cells will be well suited for the future goal of developing universally accepted, readily available tissue-engineered tracheas. The goal of the current investigation is to develop placenta stem cell based tracheal implants, and to test the implants as tracheal airway replacements in an animal model. Not only will these studies advance our knowledge of airway-related tissue engineering, but findings will enhance our understanding of placenta stem cells applicability to tissue engineering, and, if successful, these experiments would serve as landmark investigations demonstrating the first functional tissue-engineered organ derived from placenta stem cells.

"Quantifying Reproductive Transfer of Cadmium Burden in Daphnia;" Laura Wasylenki (College of Arts and Sciences) and Joseph Shaw (School of Public and Environmental Affairs)

Daphnia are small crustaceans found in lakes across the globe. Certain species have undergone rapid genetic evolution in response to heavy metal input to lakes from anthropogenic activity. Shaw and colleagues have identified a mechanism of genetic change by which some Daphnia have adapted to high levels of cadmium (Cd). Shaw seeks to further this work by sequencing genomes of preserved egg cases in lake sediment, in order to correlate the history of genetic change with Cd levels over time, but a critical assumption is that the Cd level found in an egg directly reflects the mother’s exposure to Cd. Wasylenki’s new mass spectrometer enables us to test this assumption with systematic culture experiments and analysis of Cd in single eggs.

"Self limiting Mechanisms Inhibiting Thrombus Growth;" Elliot Rosen (Shool of Medicine), Horia Petrache (School of Science) and Bogdan Dragnea (College of Arts and Sciences)

Following rupture of a blood vessel, components in blood come into contact with elements in the damaged vessel wall to form a clot to stop bleeding. The process must be tightly regulated so inappropriate clotting within vessels caused by inflammation or disease is controlled and does not lead to blockage of blood flow. The project includes experiments designed to test a hypothesis that fibrin, which is made during the coagulation process and is a major structural component providing strength to the clot, also inhibits the growth of clots following minor injury. We propose that fibrin forms a cap on the surface of the developing clot providing a barrier for the accumulation of blood components required for further growth.

"The Role Of Phototropins In Optimizing Photosynthesis In Soybean;" John Watson (School of Science) and Roger Hangarter (College of Arts and Sciences)

During photosynthesis, plants harvest solar energy to convert atmospheric carbon dioxide into sugars, which in turn powers almost all life on Earth. Plants use a class of blue light photoreceptors called phototropins to trigger a variety of responses that collectively optimize a plant’s photosynthetic activity. We propose to study phototropins and their action in soybean, with the long-term goal of improving photosynthetic efficiency in soybean and hence its productivity through genetic engineering. Enhanced yield in soybean will have significant economic benefits and will enhance human health as we enter an era when food supplies will be outpaced by the world’s population growth.

"Translational Potential of Combined Electrical Stimulation and Testosterone Treatment for Peripheral Nerve Injury Repair;" Dale Sengelaub (College of Arts and Sciences) and Kathryn Jones (School of Medicine)

While regeneration and recovery of function can be achieved when nerves are damaged, suboptimal outcomes almost always occur following injury, particularly when nerves are cut and require surgical repair. Such suboptimal outcomes diminish full rehabilitation and contribute to a prolonged decrease in quality of life issues, as well as increased risk for additional medical complications. Currently, there are no non-surgical treatment strategies in clinical use for nerve injuries. The goal of this project is to determine if a combined treatment strategy using electrical stimulation and treatment with androgens has the potential for broad application as a non-surgical treatment approach to nerve injury. This project will determine if this treatment approach can be applied to spinal nerve injuries occurring with limb damage. If so, this would validate the treatment approach across a variety of nerve injuries and support broad clinical application in general. Using behavioral, electrophysiological, and anatomical techniques, the specific aim of this proposal is to determine if electrical stimulation, in conjunction with and treatment with androgens, will improve recovery outcome following a clinically relevant sciatic nerve injury.