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Collaborative Research Grants (IUCRG) — 2015-16 Recipients

Regulation of influenza disease development through Nmp4-UPR axis: Jie Sun (Department of Microbiology and Immunology and Pediatrics-Pulmonary Research, IU School of Medicine), Ron Wek (Department of Biochemistry & Molecular Biology, IU School of Medicine), and Joe Bidwell (Department of Anatomy & Cell Biology, IU School of Medicine)

Influenza results in 3 to 5 million cases of illness and an estimated 250,000 to 500,000 deaths worldwide each year. Flu-associated death often results from collateral lung damage sustained by the body’s own inflammatory immune response. Discovering modes to alleviate this injury without compromising infection resolution is a critical barrier to treatment. We have engineered a mouse harboring a global loss-of-function mutation in the transcription factor Nmp4 that shows improved survival to influenza likely a consequence of diminished lung immunopathology. We hypothesize the loss of Nmp4 enhances the secretion of protectant lung surfactant and alters the capacity of the bone marrow to mobilize the inflammatory immune response. We will test two non-mutually exclusive models for determining how this occurs. Model 1: We will evaluate Nmp4 control of surfactant protein secretion by alveolar type 2 cells. Additionally, Nmp4 regulation of inflammatory macrophage differentiation will be assessed. Model 2: Bone marrow transplants will be performed in advance of influenza infection. The impact of Nmp4 on bone marrow capacity for mobilizing inflammatory neutrophils will be evaluated. This project is an emergent cross-collaboration between three investigators who fortuitously discovered the intersection of their different programs. Joe Bidwell, a skeletal biologist, co-discovered Nmp4 and has shown its loss converts osteoblasts into super-secretory cells. Ron Wek, a biochemist, studies cell secretion. Jie Sun studies the immune response to influenza. The anticipated data will provide a map to novel drug targets for ameliorating the morbidity and mortality precipitated by the body’s own fight against infection.

Growth and shape mechanisms in the Lyme disease pathogen Borrelia burgdorferi: Yves Brun (Department of Biology, College of Arts and Sciences, IU Bloomington) and Frank Yang (Department of Microbiology and Immunology, IU School of Medicine)

Bacterial cell shape has recently emerged as an important factor in pathogenesis. We propose to use a high throughput microscopy screen to identify genes required for the spiral shape of B. burgdorferi, the causative agent of Lyme disease. The project has three aims. In aim 1, we will generate a transposon library of ~5,000 mutants, which will provide 95% confidence that every gene has been mutated. In aim 2, the mutant library will be bound to imaging 384-well plates and screened by microscopy using a BD Pathway 855 high-content imager. Quantitative analysis of the images will be performed using the MicrobeJ automated image analysis package. Cell shape mutants will be stained using PG synthesis probes to analyze defects in peptidoglycan synthesis. In aim 3, we will use a murine Lyme disease model to test ten mutants with various morphological defects for infectivity and their ability to induce Lyme arthritis or carditis. This collaborative research with combination of expertise in bacterial morphogenesis and B. burgdorferi pathogenesis proposes to study B. burgdorferi pathogenesis from a novel angle. At the completion of the proposed work, we will have identified some of the genes that control B. burgdorferi cell shape, and we will have determined their impact on the pathogen’s ability to cause disease and persistent infection. The work will have significant impact on our understanding of B. burgdorferi pathogenesis, and will establish the foundation to develop strategies to prevent infection and treat persistence.

The U.S. Energy and Climate Transition: Aggregated Impacts of Policy on Vulnerable Populations: Sanya Carley (School of Public and Environmental Affairs, IU Bloomington), Tom Evans (Department of Geography, College of Arts and Sciences, IU Bloomington), and David Konisky (School of Public and Environmental Affairs, IU Bloomington)

The United States is in the midst of a massive energy and climate transition. This transition will be marked by improved environmental conditions as well as enhanced energy innovation. Despite these potentially significant societal benefits, this transition will also have serious implications for economically vulnerable populations within the United States. It has potential to exacerbate income inequality, disrupt labor markets, and reduce government revenue funding the social safety net. The most important impetus for this energy transition is governments’ efforts to address the problem of global climate change. Federal, state, and local governments across the country have put in place a diverse portfolio of policies to move toward a less carbon-intensive economy. These policies, however, have been developed without coordination or consideration of their effects, either independently or collectively, on vulnerable populations. Our ability to manage this transition in a way that does not leave these vulnerable groups behind will be important to the stability of our economic and social institutions, and the credibility of our energy and climate governance. In this project, we will 1) develop a conceptual framework to define vulnerability in the context of this transition; 2) examine the dimensions of vulnerability faced by U.S. households; and 3) delineate the geographic distribution of vulnerability across the country. The project will provide the foundation for future research on the effects of this transition on other parts of the economy as well as for the development of practical policy options that the government can pursue to support vulnerable groups.

Examining the cumulative effect of an Engineering-focused Workplace Simulation (WSP) on students’ understanding of, interest in and attitudes towards STEM+C disciplines: Dionne Cross Francis, (Department of Curriculum and Instruction, School of Education, IU Bloomington), Raquel Hill (Department of Computer Science, School of Informatics and Computing, IU Bloomington), Garfield Warren (Department of Physics, College of Arts and Sciences, IU Bloomington), and Walter Raymond Smith (Department of Literacy, Culture, and Language Education, School of Education, IU Bloomington).

STEM workers drive our nation’s innovation and competitiveness by generating new ideas, companies and industries. However, U.S businesses frequently voice concerns over the supply of skilled STEM workers. There is grave concern that over the next decade many of these jobs will go unfilled because current schooling is not preparing students in ways that will meet this growing demand for competent STEM professionals. We propose an innovative approach to integrated learning, called the Workplace Simulation Project (WSP), where students learn disciplinary content by inviting businesses to have a physical presence within the school building to collaborate with teachers and students to complete client-generated projects. In this learning environment students will be actively engaged in exploring science, technology, engineering, mathematics and computer science (STEM+C) concepts, which will support the development of enduring understandings of concepts while enhancing knowledge and interest in STEM+C careers; thus, developing a pipeline of individuals prepared to enter the STEM+C workforce with the necessary skills to fulfill employment needs. This project draws from the tenets of problem and project-based learning, and other valuable inquiry-based approaches, and extends them by aiming to deliver authentic academic experiences that not only teach important academic content in ways that promote problem solving and critical thinking, but also supports career exploration and the development of soft skills. We aim to investigate changes in subject-specific and integrated knowledge, and knowledge of and interest in STEM+C careers for students who are engaged in WSP and for a comparable group who are not.

Ion Selective Separators for Lithium Batteries Enabled by Anion Binding Macrocycles: Yongzhu Fu (Department of Mechanical Engineering, IUPUI) and Amar Flood (Department of Chemistry, College of Arts and Sciences, IU Bloomington).

Liquid electrolyte is the critical component of lithium-ion batteries used in portable electronics and electric vehicles. Residual anion transport in the lithium-based electrolyte results in concentration polarization, leading to capacity loss and low energy density batteries. Polymer electrolyte, using immobilized anions is one solution to these problems but usually confer low ionic conductivity. Therefore, single-ion conductors, which only conduct lithium cations, remain an outstanding goal in the battery community. Macrocycles recently discovered by CoPI Flood bind the anions common to lithium electrolyte, such as, PF6 –, with unparalleled strengths; affinities exceed all prior examples by a factor of 100,000,000. We seek, therefore, to test the central hypothesis that single-ion conductors can be made from these macrocycles such that they retain the high conductivity of liquids and the anion immobilization of polymers. This proposal, seeks to fabricate separators and test their ion selectivity, ion conductivity, and battery performance when those membranes incorporate (1) the first class of “cyanostar” macrocycles, (2) a second class of “tricarb” macrocycles, and (3) cyanostar-copolymer gels. Fu will be responsible for performance characterization, both Fu and Flood will fabricate separators, Flood will be responsible for the syntheses, and both PIs will analyze the data to evaluate how the structures of the macrocycle and the separator impact macrocycle-filled separators’ performance. The proposed strategy has the potential to enable a truly single ion conductor with high cation conductivity for practical applications. The outcomes of this project will position the team to submit high quality NSF and DOE grant proposals.

Dual targeting of cancer and chemotherapy-induced neuropathic pain by a cannabinoid CB2 receptor mechanism: Andrea Hohmann (Department of Psychological and Brain Sciences, College of Arts and Sciences, IU Bloomington) and Harikrishna Nakshatri (Department of Surgery, IU School of Medicine)

The present IUCRG grant tests the hypothesis that cannabinoid CB2 agonists represent dual targeting agents for both cancer and chemotherapy-induced peripheral neuropathic pain in mouse models of breast cancer. The proposal unites the expertise of the Nakshatri lab in breast cancer and metastasis and Hohmann lab in chemotherapyinduced peripheral neuropathy and cannabinoid pharmacology. The proposed dual targeting strategy offers the opportunity to maximize therapeutic efficacy while minimizing unwanted side effects of chemotherapeutic agents. Identification and validation of efficacious analgesics that also enhance anti-tumor activity of taxane chemotherapeutic agents would be transformative for the fields of cancer and pain management.

Virtual reality to assess and treat childhood aggression: Tom Hummer (Department of Psychiatry, IU School of Medicine), Dawn Neumann (Department of Physical Medicine and Rehabilitation, IU School of Medicine), and Zebulun Wood, (School of Informatics and Computing, IUPUI)

Aggression accompanies many childhood mental health disorders, with long-term consequences for both perpetrators and victims. To address childhood aggression in an innovative manner, we propose to utilize state-of-the-art virtual reality (VR) technology for a new tool to assess and treat childhood aggression. The long-term goal of this collaborative team is to develop a VR program with multiple purposes: as a multi-session therapy that rewards positive behaviors, as a tool to measure aggression in controlled settings, and as an aid for ongoing behavioral therapy. The first step in this process is to assess children’s ability to use and interact with a virtual environment and to examine whether interactions in the virtual world are related to cognitive, emotional, and physiological markers of aggression. To this end, children aged 8-12 will perform a virtual task (return their tray) within a realistic school cafeteria, under three distinct interpersonal scenarios: No conflict, Hostile, and Ambiguous. Wireless heart rate monitoring will occur simultaneously. After interacting in the virtual environment, children will answer questions about the realism, usability, and potential side effects of the program. In addition, we will examine whether youth high and low in real-world aggression differ in their cognitive and emotional responses to interpersonal interactions and in their heart rate during the three scenarios. In this manner, we will have feedback and preliminary data on the feasibility of VR to assess and treat childhood aggression, which will provide the foundation for ongoing development of VR therapy aimed at modifying aggressive, antisocial behavior in children.

Development of a novel technology-based self-reflection intervention for Autism Spectrum Disorder: Sarah Hurwitz (Department of Curriculum and Instruction, School of Education, IU Bloomington) and Dan Kennedy (Department of Psychological and Brain Sciences, College of Arts and Sciences, IU Bloomington)

This proposal combines the unique backgrounds and expertise of a neuroscientist and a behavioral interventionist to develop a novel, highly innovative treatment designed to improve the social abilities of children and adolescents with Autism Spectrum Disorder (ASD). Our intervention plan is innovative in several respects: (1) It is designed to teach individuals with ASD the pivotal skill of spontaneous self-reflection – that is, the ability to think about oneself in past, present, and future social contexts. Acquiring this skill will then facilitate improvement in downstream social abilities like conversational reciprocity, eye contact, and perspective taking. (2) This intervention is theoretically motivated by neuroscience research showing dysfunction of the Default Mode Network in people with ASD, a brain network critical for processing social information and self-reflection. (3) The treatment itself integrates technology in a unique way, and is particularly appealing for people with ASD. Special video-recording eyeglasses will be used to chronicle real social interactions from two different first-person perspectives. These videos, together with question prompts, will serve as training tools to teach participants to spontaneously self-reflect, thus allowing for continual improvement of their social abilities over time. With this grant, we plan to develop and test the effectiveness of an 8-week social skills intervention for children and adolescents with ASD, at the same time generating pilot data for an external grant submission aimed at expanding the project’s size, setting (e.g., home, school, community), and scope (i.e. by using functional neuroimaging to identify and track brain-based biomarkers in the Default Mode Network).

Structure Function-Analysis of a Nucleotide Binding Leucine-Rich Repeat Immune Receptor: Roger Innes (Department of Biology, College of Arts and Sciences, IU Bloomington) and Yuichiro Takagi (Department of Biochemistry and Molecular Biology, IU School of Medicine)

Intracellular receptors characterized by the presence of a Nucleotide binding domain and Leucine rich Repeats (NLRs) play a central role in the innate immune systems of plants and mammals, including humans. Understanding how NLR proteins mediate pathogen detection and activate immune responses is a major focus of the Innes laboratory at IU Bloomington. Work in the Innes laboratory has established that the NLR protein RPS5 from Arabidopsis mediates detection of a cysteine protease named AvrPphB, which is injected into host cells by the pathogenic bacterium Pseudomonas syringae. This work has led to multiple high impact publications, including three in Science. Further progress on this system, however, requires that we obtain a structure for RPS5. To date, no structures for a plant NLR protein have been reported, due to an inability to overexpress these proteins in soluble form. To overcome this bottleneck, the Innes laboratory is collaborating with the Takagi laboratory at the IU School of Medicine. Dr. Takagi’s lab has developed a novel protein expression system that enables expression and purification of particularly difficult proteins. Our preliminary data show that this system works well for the overexpression of RPS5. We now propose to determine its structure using cryo-electron microscopy. Cryo-EM work will be performed in collaboration with the IUB Electron Microscopy center, which has a state-of-the-art cryo-electron microscope that will enable structure determination at unprecedented resolution. A structure for RPS5 will open up multiple new avenues of research that should be highly fundable by both the NIH and NSF.

Harnessing human perception and gesture to develop sharable expertise in algebra: Erik Jacobson (Department of Curriculum & Instruction, School of Education, IU Bloomington) and David Landy (Department of Psychological and Brain Sciences, College of Arts & Sciences, IU Bloomington)

Perception—how sensory information is selected or ignored—is a hallmark of expertise from chess grandmasters to sommeliers. Perception may also distinguish expertise in more abstract domains such as mathematics. School algebra begins in the elementary grades and involves coordinating different representational systems including graphs, equations, and verbal descriptions to understand abstract concepts like linear function. A key challenge for teaching and learning is that any particular representation within a system is just one member of a set of algebraically equivalent but perceptually dissimilar representations. For example, the scale of the x-axis affects the perceptual steepness of a linear graph but not the function’s rate of change. Human perception can be rapidly trained to perceive invariance across wide perceptual variability, but perceptual learning is largely unconscious, introducing two problems: perceptual expertise may be difficult to integrate with explicit knowledge and may confound rather than enhance teachers’ explanations. Growing evidence suggests kinesthetic action grounds abstract ideas, improves conceptualization, and increases gesturing—a critical modality for mathematics teaching and learning. Our IUCRG project will recruit undergraduate education majors to experimentally test whether kinesthetic perceptual learning improves integration with conceptual knowledge and enhances the communicability of resulting perceptual expertise relative to nonkinesthetic perceptual learning. Data will include standard measures of perceptual and conceptual learning and novel measures of shareable expertise, such as gesture frequency and elementary student learning in response to undergraduate explanations. This pilot is the first step towards understanding how means of gaining perceptual expertise influence the ability to share it.

Characterization of mitochondria and their interaction with Stat3 in osteoblasts and osteocytes: Jiliang Li (Department of Biology, School of Science, IUPUI) and Nickolay Brustovesky (Department of Pharmacology and Toxicology, IU School of Medicine)

Mechanical loading is required for maintenance of the musculoskeletal system. Yet, the molecular mechanisms underlying bone mechanotransduction are incompletely understood. The existing bone studies are mainly focused on events in the nucleus, and little attention has been placed on the potential role of mitochondria in osteogenesis. Conditional deletion of Stat3 in both osteoblasts and osteocytes (Stat3OB-/- and/or Stat3OCY-/- mice) suppressed load-induced bone formation in mice. Stat3 deficiency in osteoblasts elevated reactive oxygen species (ROS). Those data suggest a potential role of Stat3 in bone mitochondria and responsiveness to mechanical stimulation. We propose two specific aims of the IU CRG period: 1) Determine the role of Stat3 signaling in mitochondria of osteoblasts and osteocytes, and 2) Examine the effect of oxidative stress on bone mechanical responsiveness. Aim 1 will employ the primary osteoblasts and osteocytes from Stat3OB-/- and Stat3OCY-/- mice, as well as Stat3 KO BMSC line to determine the role of Stat3 in regulation of mitochondrial oxidative metabolism. Additionally, we will determine the effect of Stat3 phosphorylation on the mitochondrial functions. Aim 2 will employ Stat3OB-/- and Stat3OCY-/- mice as well as their littermate WT mice. We will apply ulna loading, in the presence and absence of the antioxidant scavenger, N-acetylcysteine (NAC), to clarify the linkage of mechanoransduction and oxidative stress. This project will enable us to elucidate regulatory effects of Stat3 on bone mitochondria in response to loading and gain new insights into molecular mechanisms related to load-driven osteogenesis.

Understanding Emergency Department Operational Behaviors: A System Approach: Shuning Li (Department of Engineering Technology, School of Engineering & Technology, IUPUI) and Hazim El- Mounayri (Department of Mechanical Engineering, School of Engineering & Technology, IUPUI)

Emergency departments (EDs) are an essential component of healthcare delivery system in the US, especially to our most vulnerable populations. EDs face unique challenges including crowding, over use, and resource and cost containment; and the situation has reached epidemic proportions in terms of threats to the safety and quality of healthcare delivered in the emergency care setting. Understanding the ED operational behaviors is the key first step to find solutions for these challenges. Our proposed study is using a novel system approach to address fundamental, unmet needs for EDs. Two kinds of models will be developed: systems models and simulation models. Systems models focus on eliciting stakeholder requirements and build comprehensive views of the system by using the techniques of the DoD Architecture Framework (DoDAF). Two use cases (the intoxicated suicidal patient and COPD patients) have been developed by the research team to support the development of systems models. Simulation models will be built at two levels: general “black box” model and use case simulation models by using Tecnomatix Plant Simulation, a leading process simulation platform. The general model will be used to provide estimations to the effects on the change of staffing and other resources, and help the allocation of ED resources, defining the cost of healthcare delivered. Use case simulation models will provide more process details; and be used to quantify the value of healthcare delivered. Our study will be conducted in the Michael & Susan Smith Emergency Department (ED) of Eskenazi Healthcare System.

A Search for New Spin-Dependent Forces At Micron Scales Using Ultracold Atoms: Josh Long (Department of Physics, College of Arts and Sciences, IU Bloomington), Le Luo (Department of Physics, School of Science, IUPUI) and Mike Snow (Department of Physics, College of Arts and Sciences, IU Bloomington)

The possible existence of new weak forces of nature with ranges of macroscopic scale (nanometers to millimeters) is attracting increased scientific attention. We propose to test the hypothesis that such forces exist by conducting extremely sensitive searches for possible new forces over this range using ultracold atom clouds chilled to 1K temperature recently developed at IUPUI. Based on the spectacular success of a previous IUB/IUPUI IUCRG proposal in later attracting NSF funding, we strongly feel that the odds are good that the successful completion of this project will help attract new funding to IU. In our experiments, ultracold lithium atoms will be trapped in front of a structured material composed of an alternating series of Au and a spin polarized, zero magnetization material. The structured sample is oscillated with respect to the trapped atoms. An exotic fifth force would modify the trapping potential of the cold atoms and thereby allows for detection. These ultracold atoms experiments provide tremendous advantages over other methods to sense very weakly interacting light particles. In particular, the different spin states of the isotope of lithium (6Li) can be trapped close to the sample, which is perfect for probing spin dependent effects. The implications of these measurements for analysis of possible new spin-dependent effects in gravity which violate CPT and Lorentz symmetry are already under development at IUB. We ask for support for a student and a postdoc to work on key technical issues needed to demonstrate the sensitivity of our experimental techniques.

Overcoming barriers to optic nerve regeneration: Jason Meyer (Department of Biology, School of Science, IUPUI) and Maria Grant (Department of Ophthalmology, IU School of Medicine)

This proposal examines the ability of induced pluripotent stem cell-derived retinal ganglion cells to regenerate the neural connections in the optic nerve. As the connection between the eye and the brain, damage to the optic nerve results in vision loss and blindness. Cell replacement with human induced pluripotent stem cell-derived retinal ganglion cells provides an attractive means of therapeutic intervention. However, many obstacles exist that may impede success of such an endeavor. The proposed studies serve to address and overcome these barriers in both in vitro and in vivo systems, thereby increasing likelihood for success and serving as a platform for future studies and grant applications.

Modulating the cellular and structural mechanisms underlying craniofacial development in Osteogenesis Imperfecta: Jason Organ (Department of Anatomy and Cell Biology, IU School of Medicine) and Rachel Menegaz (Department of Biomedical and Applied Sciences, IU School of Dentistry)

Osteogenesis imperfecta (OI) is a genetic disorder that causes brittle bones and increased risk of skeletal fracture. OI patients, many of whom are children, also suffer from underdeveloped facial bones and dental malocclusions, the causes of which are poorly understood. This project will investigate the developmental and physiological basis for facial abnormalities in a mouse model of OI, and test the hypothesis that a soft diet, like the one consumed by weaning children, contributes to the under-use and thus the under-development of the jaws and chewing musculature. This research is the first step in investigating a combination behavioral-drug intervention for facial disorders in OI, with the goal of transforming the dental care of OI patients by providing a preventative alternative to the current orthodontic treatments.

Biological mechanisms underlying the relationship between social networks and age-related cognitive decline: Brea Perry (Department of Sociology, College of Arts and Sciences, IU Bloomington) and Andrew Saykin (Department of Radiology and Imaging Sciences, IU School of Medicine)

Dementia affects 1 in 9 adults over 65, and the prevalence is expected to triple by 2050. Agerelated cognitive decline takes a devastating toll on families, and contributes to rising costs of healthcare. A critical point of intervention is the social environment, which may moderate the typical cognitive course of dementia. Social engagement is associated with reduced risk for Alzheimer disease (AD) and a slower trajectory of age-related cognitive decline. However, little is known about the biological mechanisms underlying this relationship. In the proposed project, pilot social network data will supplement existing biomarker data (e.g. neuroimaging, cerebrospinal fluid) and clinical cognitive assessment. The resulting dataset will provide an opportunity to examine interactions between multiple levels in a complex system. Social network data will be collected from patients with mild cognitive impairment (MCI, n=48), AD (n=98), and healthy age-matched controls (n=172) who are research participants at the Indiana Alzheimer Disease Center. Specific aims are to: 1) Examine relationships between characteristics of social networks, underlying pathology, and clinical indicators of cognitive status in older adults; and 2) Determine whether changes in underlying biological pathology mediate or moderate the influence of social networks on rate of cognitive decline and/or clinical progression of Alzheimer disease and dementia. By increasing our understanding of the link between biological and social processes in the neurology of aging, this project will help identify novel targets for intervention to reduce the burden of AD and age-related cognitive decline on individuals, families, and the health care system.

Using in-situ acoustics and mathematical models to evaluate middle ear reconstructive surgery: Robert Withnell (Department of Speech and Hearing Sciences, College of Arts and Sciences, IU Bloomington) and Charles Yates (Department of Otolaryngology, Head and Neck Surgery, IU School of Medicine)

Surgical reconstruction of the middle ear and ossicular chain following damage to middle ear structures by disease processes such as cholesteatoma or chronic middle ear infection is a common procedure that will be required by approximately 1 in 10,000 people. This reconstruction is informed by clinical experience as well as concepts that pre-date modern medicine (Helmholtz, 1860’s). To replace the ossicles, Otolaryngology surgeons have a choice of prostheses that vary in size, length, and mechanical properties. This study will investigate which of these factors are important for restoration of hearing using a resonant circuit model of the middle ear and acoustical measurements in the ear canal pre and post middle ear reconstruction.

Investigating the cellular and molecular mechanisms underlying autosomal recessive Retinitis Pigmentosa 25: Andrew C. Zelhof (Department of Biology, College of Arts and Sciences, IU Bloomington), James Marrs (Department of Biology, School of Science, IUPUI), and Ryan Anderson (Departments of Pediatrics and Cellular and Integrative Physiology, IU School of Medicine)

Retinitis Pigmentosa (RP) is characterized by the degeneration of rod and cone photoreceptor cells and can be inherited in X-linked, autosomal recessive and dominant fashions. In today’s world of genomics, rapid progress has been made in identifying genes responsible for many Retinitis Pigmentosa conditions. However, the challenge remains to make new progress toward effective therapeutic intervention, which will require better understanding of the molecular and cellular role of these gene products in normal and diseased photoreceptors. Furthermore, given the complexity of the human retina, these advancements will require the use of genetically amenable model systems. Mutations in the human gene EYS are responsible for autosomal recessive Retinitis Pigmentosa 25 (arRP25), which account for ~5% of all autosomal recessive RPs. Despite the fundamental differences in photoreceptor structure, EYS expression in photoreceptors is conserved from flies to humans. The goal of this research collaboration is to link the initial Drosophila studies of EYS with a vertebrate model, zebrafish, of retina development. Since EYS is absent in rodents, these animal models are not beneficial. This project will generate an effective combinatorial approach to dissect the cellular and molecular mechanisms of EYS function in both wild type and diseased photoreceptors. At the completion of these studies, we expect to have established a basic understanding of EYS function to permit the future development and testing of potential models of therapeutic intervention for the treatment of arRP25.