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Collaborative Research Grants (IUCRG) — 2014-15 Recipients

Single Cell Studies with Scanning Sniffer Patch Microscopy: Lane Allen Baker (Department of Chemistry, College of Arts & Sciences, IU Bloomington) and Theodore Cummins (Department of Pharmacology & Toxicology, IU School of Medicine)

This project aims to develop a new mode of microscopy that responds to chemical/biochemical stimulants with high selectivity, and with subcellular spatial resolution, without the need to incorporate fluorescent labels or radiolabels. We term this tool Scanning Sniffer Patch Microscopy. To realize this technology, we will incorporate ion channels present in excised cell patches that are positioned at a cell/tissue interface with scanning ion conductance microscopy. This project will bridge biological/biochemical research at the STARK Neuroscience Research Institute and in Pharmacology/Toxicology at the Indianapolis campuses to analytical/instrumentation research in the Chemistry Department at Bloomington. Importantly, this bridge capitalizes on strengths of research excellence for each campus, and is targeted to develop tools and models for new modes of bioanalytical/biophysical measurement.

Investigating the Relationship between Cumulative Disadvantage and Telomere Length as a Contributor to Cancer Disparities: Silvia Bigatti (Department of Social & Behavioral Sciences, Richard M. Fairbanks School of Public Health, IUPUI), Brittney-Shea Herbert (Department of Medical & Molecular Genetics, IU School of Medicine), Kenzie Latham (Department of Sociology, School of Liberal Arts, IUPUI), and Anna Maria Storniolo (Department of Medicine, Division of Hematology/Oncology, IU School of Medicine)

Breast cancer mortality rates for African American women are higher than in White women, and incidence among young African American women is higher and more aggressive than in White women. Over the course of one's life, social, economic, and person-related disadvantages add up and compound – a concept we refer to as cumulative disadvantage (CD). This can result in chronic stress that wears down the body, ages cells, and shortens telomeres – caps on the ends of chromosomes - leading to genetic instability. Shortened telomeres have been associated with several negative health outcomes, including cancer incidence and mortality, independent of usual cancer risk factors. CD may explain, in part, the substantial and persistent disparities in breast cancer experienced by African American women. The goals of this pilot study are to compile a valid and reliable battery of questionnaires to measure CD, and to assess preliminary correlation between CD and telomere length, a biomarker of cellular age and fitness in this study. We will conduct interviews, administer surveys, and measure telomere length among 15 white and 15 African American women of varying education levels. Exploring the association between CD and shortened telomere length may advance understanding of the impact of social and behavioral processes on breast cancer disparities, as well as health disparities beyond cancer. This research team has the potential to contribute valuable knowledge about the interplay between genetic and social environments, and specifically how social influences are embodied and result in ill health.

Mechanism of the Regulation of DNA replication by PIF1 Family Helicases: Matthew L. Bochman (Department of Molecular & Cellular Biochemistry, College of Arts and Sciences, IU Bloomington), Yuichiro Takagi (Department of Biochemistry & Molecular Biology, IU School of Medicine), and Amber Mosley (Department of Biochemistry & Molecular Biology, IU School of Medicine)

DNA is a double-stranded molecule that contains all of the genetic "information" necessary for life. The replication of DNA is an essential process for all cells to grow and divide, and replication depends on separating the duplex DNA molecule into single strands, which are subsequently copied. The enzymes responsible for DNA strand separation are known as helicases. As a vital process, it is perhaps unsurprising that many human diseases, such as cancer, are due to perturbations in DNA replication, and mutations in the genes that encode helicases are often also disease-linked. In other words, when helicases function properly, they act as tumor suppressors in cells. However, helicases are also multifunctional, and it is unclear why a given mutation may lead to cancer at a mechanistic level. To gain insight into these issues and compete for funding in this active research field, the collaborative study by the Bochman, Takagi, and Mosley groups will use diverse biochemical and proteomic techniques to determine how PIF1 family helicases regulate DNA replication. PIF1 helicases are found in most organisms and are crucial to genome integrity. Indeed, mutations in the human PIF1 (hPIF1) helicase are linked to various cancers. Our team aims to purify the hPIF1 protein for the first time and directly examine its biochemical activities in isolation. We also plan to determine if hPIF1 interacts with other protein partners in the cell and how these interactions modulate hPIF1 activity. Ultimately, this research could lead to new cancer drug targets.

Matrix Engineering with Adipose Stem Cells to Promote Islet Function and Longevity: Robert V. Considine (Department of Medicine, Division of Endocrinology, IU School of Medicine), Raghu Mirmira (Department of Pediatrics, IU School of Medicine), and Sherry L. Voytik-Harbin (Department of Biomedical Engineering, Weldon School of Biomedical Engineering, Purdue University)

Type 1diabetes affects nearly 3 million individuals in the U.S. and is the third most common chronic health condition among American youth. In this disease the insulin-secreting β-cells within the pancreatic islets are destroyed, resulting in an inability to regulate blood sugar. Transplanting islets can correct diabetes, but this intervention is currently not durable as islet survival is limited. Thus there is an urgent need for tissue engineering approaches to improve the function and longevity of islet transplants. Transplanting islets contained within collagen-based scaffolds can improve transplant survival. Our group has developed a novel set of collagen polymer building blocks that provide control over matrix microstructure, stiffness, and degradability, all factors known to influence cell fate. This novel matrix preparation provides a means to advance islet transplantation by improving islet function and survival. Adipose stromal cells (ASC), a type of mesenchymal stem cell isolated from the subcutaneous adipose tissue, may be a useful addition to collagen based islet transplants. ASC secrete a large number of growth factors that promote islet function and longevity, and which also stimulate vascular development, reducing hypoxia and promoting survival of transplanted islets. Thus the overall goal of this study is to co-culture ASC with islets in optimized collagen matrix to build long-lived functional tissue implants with proven ability to lower blood sugar in diabetic animal models. Basic knowledge derived from these studies will be applicable to development of islet transplants to treat diabetes in humans.

Using in vivo Microscopy to Build Predictive Models of Drug-Induced Liver Injury: Kenneth Dunn (Department of Medicine, Division of Nephrology, IU School of Medicine), Richard Day (Department of Cellular & Integrative Physiology, IU School of Medicine), and Steve Pressé (Department of Physics, School of Science, IUPUI)

Predicting the adverse effects of drugs on the liver is a major challenge in drug development. The inadequacy of current approaches is reflected by the fact that drug-induced liver injury is the most common cause for withdrawal of drugs from the market. We have demonstrated that intravital microscopy (fluorescence microscopy of the organs of living animals) is capable of identifying how drugs affect liver transport in the context of the living animal. The goal of our project is to provide the analytical foundation necessary to realize the potential of intravital microscopy as a tool for determining how drugs affect the liver. We will develop an experimental platform that will provide more accurate, reproducible measures of transport, including pathways that cannot be observed by other methods. The larger impact of the project will be the derivation of a novel integrated model of liver transport, based upon transport parameters measured in vivo, that will provide a bridge between studies conducted in cultured cells and studies conducted with animals. This could allow data collected in high-throughput screens to more accurately predict effects on laboratory animals. Our approach has the potential to increase the physiological relevance of high-throughput studies in ways that could be transformative for preclinical evaluations of hepatic drug effects -- extending the predictive power of in vitro drug development studies, minimizing the numbers of animals needed for in vivo studies and reducing the number of drug failures.

Understanding Naturalistic Bicyclist Behavior for Safety and Sustainability: David Good (School of Public and Environmental Affairs, IU Bloomington), Lauren Christopher (Department of Electrical & Computer Engineering, School of Engineering & Technology, IUPUI), Stanley Chien (Department of Electrical & Computer Engineering, School of Engineering & Technology, IUPUI), Jiang Zheng (Department of Computer & Information Science, School of Science, IUPUI) and Yaobin Chen (Department of Electrical & Computer Engineering, School of Engineering & Technology, IUPUI)

Around the world, approximately 1.2 million people per year are killed in traffic crashes. Among developed countries, the fraction killed in bicycle related incidents varies widely, from about 3% in the US to 24% in the Netherlands. While there is a rapidly increasing amount of data being accumulated regarding naturalistic driving (from in-vehicle cameras and other sensors on the driver, vehicle and surroundings) about driver behavior, relatively little is known about cyclist behaviors and the risks they are willing to take. Our pilot study will fill this gap by instrumenting a number of bicycles and following the behaviors of riders as they go about their typical riding travel. This instrumentation includes some innovative technologies such as a micro-fluidic lens camera. By rapidly focusing and de-focusing the lens of the camera, the distance to objects in the image can be recovered. This replaces bulkier and more power consuming sensors like radar without information loss. Other instrumentation included in the data acquisition equipment are a wide angle lens, camera on the cyclist, GPS location and 9 degree of motion accelerometers. The study is expected to result in massive amounts of data, approximately 100TB. This will be analyzed with pattern recognition algorithms used to understand risk taking, evaluating acceptable gaps for oncoming vehicles, when the rider decides to run stop signs or signals, and how these behaviors may be related to rider fatigue.

Neurotherapeutic Potential of Adipose Stem Cell-Conditioned Medium in ALS: Kathryn Jones (Department of Anatomy & Cell Biology, IU School of Medicine) and Keith March (Department of Medicine, Krannert Institute of Cardiology, IU School of Medicine)

Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure or treatment. ALS involves gradual and irreversible loss of motoneurons within the brain and spinal, and is accompanied by axonal die-back and disconnection from peripheral musculature. This axonal die-back precedes and may initiate the loss of motoneurons, and is partially responsible for the relentless and fatal paralysis associated with the disease. One compelling reason why treatments for ALS repeatedly fail is they may only be targeting one facet of the disease, i.e., motoneuron survival within the brain and spinal cord. If axonal die-back and loss of neuromuscular junctions persists in the periphery, then paralysis will continue unabated and the disease will be fatal. The Jones Laboratory is devoted to motoneuron biology and the March Laboratory focuses on adipose stem/stromal cells (ASC), available by minimally-invasive liposuction, therapy. We have exciting new preliminary data demonstrating that systemic ASC-conditioned medium (CM) treatment after symptom onset in the mSOD1 ALS mouse model slows disease progression and enhances motoneuron survival. The objective of this pilot proposal data is to determine if ASC-CM has the potential to simultaneously support motoneuron survival within the CNS, and enhance neuromuscular junction preservation peripherally. If so, this would be a novel discovery with significant therapeutic potential to alter ALS disease onset and/or slow progression because both pathologies, motoneuron loss centrally and axonal die-back from muscle peripherally, can be targeted by a single treatment.

The Impact of the Public Investment in Education in the Academic Performance of K-12 English Language Learners in Southern Indiana: Haeil Jung (School of Public & Environmental Affairs, IU Bloomington), Magdalena Herdoíza-Estévez (School of Education, IU Southeast), Cathy Johnson (School of Education, IU Southeast), and Jacquelyn Singleton (School of Education, IU Southeast)

A collaborative network between school corporations, public school personnel, and families has been working since 2007 in southern Indiana. The New Neighbors Education Center, as part of the IU Southeast School of Education, with a US Department of Education grant (2007-2013) has led this endeavor directed to improve the learning environment in selected public schools in order to increase the academic performance of English Language Learners (ELLs). However, the degree of association between the multiple intervention strategies that have been implemented and the ELLs' academic performance is not rigorously studied. The present IUCRG provides an opportunity to design a longitudinal study to establish and examine sound associations between targeted intervention for ELLs and their academic performance. The research aims at providing a solid rationale for public investment in the education of ELLs in the long term, by allowing policy makers to consider and select the most efficient and effective combination of educational strategies. Also, practitioners will be able to access reliable information on the value of accommodations for ELLs, directed to improve their academic engagement and performance. The team of investigators from IU Southeast and SPEA intend to evaluate the effectiveness of the following components: a) Professional development in English as a new language best practices, and cultural competency for teachers, and para-professionals; b) Family involvement program; c) Youth motivation and tutoring program; and d) Coaching for teachers. This research aims at contributing to the discussion about investment in public education for ELLs as an effective policy measure, which propels the academic success of all learners, and creates opportunities for social progress and equity in Sothern Indiana communities.

Developing Remote Sensing Techniques for Detection of Toxin-Producing Cyanobacteria: Lin Li (Department of Earth Sciences, School of Science, IUPUI), Kevin Mandernack (Department of Earth Sciences, School of Science, IUPUI), and David Kehoe (Department of Biology, College of Arts & Sciences, IU Bloomington)

Water quality is critical to human, public and environmental health. With natural world population growth, potable sources of water are expected to become limiting by 2025. This places added urgency on all municipalities to better utilize our existing water resources. Blooms of cyanobacteria are one of the most important issues concerning water authorities and public health organizations. Recent reports predict that such blooms will become increasingly problematic in response to global climate change. These blooms are common in lakes and reservoirs nationwide that serve as sources of freshwater to many municipalities. Cyanobacteria can produce toxins that are life threatening, and taste/odor compounds that degrade water quality. Thus, cyanobacteria in surface water systems pose a serious health concern across the globe. Cyanobacteria blooms have been observed in Lake Erie almost annually in recent years. Despite their adverse environmental, economic, and public health impacts, water resource managers lack a reliable monitoring tool capable of warning about the occurrence and spatial distribution of cyanobacterial blooms. The main goal of the project proposed is to develop a remote sensing protocol to predict cyanobacterial blooms in Eagle Creek Reservoir (ECR), one of the major drinking water resources for Central Indiana which frequently experiences cyanobacterial blooms. This investigation is based on fundamental concepts in aquatic ecology, environmental microbiology, cellular biology, genetics and remote sensing. The results of this multidisciplinary investigation will lead to improved monitoring of the cyanobacterial blooms in other Indiana drinking water bodies and the Great Lakes, and have important societal benefits.

Effect of Antarctic Weathering on Global Climate: Kathy Licht (Department of Earth Sciences, School of Science, IUPUI) and David Bish (Department of Geological Sciences, College of Arts & Sciences, IU Bloomington)

Chemical weathering is the process by which rocks and sediment dissolve and form clays and mineral oxides. It is one of the primary paths by which CO2 leaves Earth's atmosphere and is sequestered in geologic reservoirs, including deposition of carbonates in the ocean. These carbonate minerals remain in the world's oceans on a time scale of millions of years, allowing weathering to cause long term changes in global climate. Antarctica should, in principle, experience very little chemical weathering due to its ice cover and the extreme cold and dry conditions. However, rocks and sediments on the continent often have a strongly weathered character. While such weathering may have occurred prior to glaciation, recent work has suggested that insulation and microbial activity allow for active chemical weathering processes beneath Antarctica's ice sheet. Because Antarctica represents 10% of the world's landmass, even modest chemical weathering rates have potentially significant climate impacts. Our IUCRG project aims to test whether Antarctic weathering occurs subaerially, subglacially, or predates glacial conditions. We will rigorously measure the quantity of chemical weathering products in Antarctic soils whose ages range from 5,000 to c. 500,000 years. This will allow us to examine the rate of change in these aerially exposed soils, and constrain the proportion of the total weathering that occurs in subaerial environments. Where the total weathering of Antarctic sediments exceeds these rates, either preglacial or subglacial weathering is suggested. Our IUCRG results will serve as the foundation of a larger project constraining weathering rates in Antarctica.

A Novel Approach to Discover Drug Resistance Genes in Breast Cancer Cells: Tao Lu (Department of Pharmacology & Toxicology, IU School of Medicine) and Lang Li (Department of Medical & Molecular Genetics, IU School of Medicine)

Breast cancer (BC) ranks second as a cause of cancer death in women. Chemotherapy has a well-established role in the management of BC. However, drug resistance has been a huge hurdle to BC treatment. This proposal, using multiple BC cells with different backgrounds as models, and employing the highly innovative validation-based insertional mutagenesis (VBIM) technique in combination with high throughput screening (HTS), RNA deep sequencing (RNAseq), and bioinformatics approaches, aims to discover a spectrum of novel resistance genes for several most standard BC chemotherapy drugs, and to build up a complete common core gene network for drug resistance in BC. The findings generated from study will have great significance at multiple levels: 1) This novel approach could yield completely novel drug resistance genes which otherwise may not be discovered with traditional approaches. 2) It will serve as a reference platform of drug resistance genes that will help physicians to predict which BC patient is drug resistant based on the patient's specific gene expression profile. 3) It would guide physicians to design more rational and precise therapies with a greater likelihood of effectiveness in a specific BC patient. 4) Moreover, our study would yield the mechanisms of gene-mediated drug resistance so that reversal of this resistance can be achieved by developing small molecule inhibitors in BC. If successful, this project will lead to novel therapeutic target discovery and will have transformative effects on BC treatment.

Induction and Maintenance of Chronic Migraine: Regulation of TRP Channels by Endogenous N-acyl Amide Lipids: Gerry Oxford (Department of Pharmacology & Toxicology, IU School of Medicine), Heather Bradshaw (Department of Psychological & Brain Sciences, College of Arts & Sciences, IU Bloomington), and Joyce Hurley (Department of Biochemistry & Molecular Biology, IU School of Medicine)

Chronic migraine is a debilitating disorder with a spectrum of symptoms and a variety of triggers and predispositions, yet we still do not understand the factors that drive the transition from acute to chronic migraine. Migraine represents a vicious cycle of elevated brain surface blood flow and hyperactivity of associated sensory nerve endings. To provide a platform to both understand the genesis of migraine and explore novel prophylactic or symptomatic therapies, we have developed an animal model of chronic migraine. In this model, brain surface blood flow elevations in response to inhaled irritants known to trigger headaches are precisely measured as a surrogate for acute migraine symptoms. We have recently extended this model by exposing animals to low, non-irritating levels of airborne environmental toxicants for several days and find subsequent vascular responses to be exaggerated, just as in humans chronically exposed to low level triggers like contaminated building materials. The molecular mechanism underlying this acute-to-chronic migraine transition is unknown. Our project will seek a possible link between a novel class of lipid molecules known to stimulate the same sensory nerves involved in the response. Following chronic irritant exposure, levels of over 70 such lipids will be measured in relevant brain regions using advanced mass spectroscopic methods. Lipids demonstrating elevations will be candidate agents mediating the genesis of chronic migraine. This concept will then be directly tested by determining the ability of candidate lipids to stimulate or sensitize the relevant sensory nerves controlling brain surface vascular responses.

Optical-Based, Label-Free Multiplex Assay for Direct Quantification of microRNAs in Serum and Cancer Cells: Rajesh Sardar (Department of Chemistry & Chemical Biology, School of Science) and Murray Korc (Department of Medicine, Division of Endocrinology, IU School of Medicine)

MicroRNAs (miRs) are small noncoding RNAs that regulate mRNA stability and/or translation. Due to their release into the bloodstream and their remarkable stability, miR levels in the circulation and other biological fluids can serve as diagnostic and prognostic disease biomarkers. However, quantifying miRs in the circulation is challenging due to sensitivity and specificity issues. Our long-term research goal is to fabricate an ultrasensitive, reproducible, optical-based sensor for detection of miRs in general and miRs in the serum of cancer patients and pancreatic ductal adenocarcinoma (PDAC) patients in particular. We will pursue three aims in the current proposal: (1) Design and characterize a regenerative, optical-based sensor utilizing gold nanoprisms that will enable the detection of attomolar concentrations of miRs in serum, representing a huge advance in the microRNA detection field. (2) Assay miR-10b in serum from patients with PDAC to confirm that serum can be used for diagnosing PDAC. (3) Quantify miR levels in cultured human pancreatic cancer cell lines and in the media from the cells to determine whether our ultrasensitive assay can be used to identify metastatic cells in the circulation and to determine whether these cells also release miRs into the bloodstream. We propose that our label-free detection of miRs in biological fluids and cancer cells can be applied to many cancer types (breast, lung, colorectal, and prostate) and could be used to assay miRs in all kinds of biological fluids (serum, plasma, whole blood, urine), and should allow a rational design of a medical device for testing the utility of miRs as markers for early disease diagnosis and prognosis.

Developmental Adaptation to Chronic Hypoxia: Robert Tepper (Department of Pediatrics, IU School of Medicine), Mircea Ivan (Department of Microbiology & Immunology, IU School of Medicine), and Kenneth Nephew (Medical Sciences Program, IU School of Medicine, IU Bloomington)

Individuals living at high altitude must adapt to the low amount of oxygen in the air (chronic hypoxia) by increasing oxygen transport to tissues in the body and altering the function and growth of different cells and organs in the body. Adults living at high altitude have bigger lungs and increased oxygen carrying capacity in the blood, while they are generally smaller in size compared to subjects living at sea level. We believe that chronic hypoxia stimulates adaptive processes very early in life and we propose a novel study of infants born in the high altitude environment of the Andes Mountains of Argentina. The proposed study is the first to examine whether adaptive molecular processes occur in the fetus during pregnancy at high altitude and persist after birth. The results of our study will contribute to a greater understanding of high altitude development and molecular responses to chronic hypoxia very early in life. Importantly, this study may drive the development of novel therapeutic strategies to stimulate lung growth and treat hypoxia-associated cardiorespiratory diseases.

Hippo/YAP Signaling Controls Protein Redistribution and Organ Size in Critical Illness: Clark Wells (Department of Biochemistry & Molecular Biochemistry, IU School of Medicine), Teresa Zimmers (Department of Surgery, IU School of Medicine), and Leonidas Koniaris (Department of Surgery, IU School of Medicine)

The physiologic responses that promote survival following severe trauma require profound metabolic alterations that are associated with protein catabolism in skeletal muscle and protein synthesis in the liver. This study will investigate how proteolysis in skeletal muscle may provide the amino acids that are necessary in the liver for the synthesis of acute phase proteins in adaptive response that limit tissue injury and aid wound healing. This will involve the elucidation of a mechanism where cells in muscle and liver may utilize a common signaling pathway to drive either a catabolic or anabolic response. This information could indicate a change in the treatment paradigm for cachexia in response to burns or trauma to restrict liver growth rather than inhibit muscle protein catabolism. Such findings may also have implications in several other diseases including cancer (e.g. in colon cancer resulting from inflammation), regeneration (e.g. promoting liver growth after transplantation), and in chronic inflammatory conditions.