Robert E. Anderson, M.D., Ph.D. - US grants

It has been shown in a number of tissues that certain types of extracellular stimuli cause an interconversion of plasma membrane lipids. Two examples are the rapid hydrolysis of inositol phospholipids and the transmethylation of phosphatidylethanolamine to phosphatidylcholine. The former, known as the "PI effect", is associated with stimulus-coupled secretion reactions which utilize Ca++ as a second messenger. The latter has been associated with the activation of adenylate cyclase. We have demonstrated the PI effect in the retina of Xenopus laevis. Light is the stimulus and the effect is in the horizontal cells. We have also demonstrated the transmethylation reaction in frog photoreceptor cells in vivo, but we have not established a stimulus dependency. We are proposing to study the metabolism of retinal membrane phospholipids, with most of our efforts directed towards investigating the physiological role of the PI effect and the transmethylation reactions. These studies will be carried out on whole retinas from Xenopus, and humans, isolated horizontal cells from goldfish, and a metabolically competent, truncated rod cell (RIS-ROS) preparation from goldfish. In retinas, we will use biochemical techniques to identify the precise inositol phosphatide(s) involved in the PI effect. The neurotransmitter(s) responsible for the intercellular communication between photoreceptor and horizontal cells will be identified. The participation of other retinal neurotransmitter candidates in provoking the PI effect in other retinal neurons will be investigated. We will utilize isolated horizontal cells to study the PI effect at the cellular level and attempt to define its role in metabolic events specifically identified with these neurons (i.e. dopamine-sensitive adenylate cyclase, potential-dependent release of GABA, or Ca++ dependent regenerative voltage responses). In the RIS-ROS, inositol phosphatides and phosphatidic acid will be examined for a role in Ca++ translocation associated with photon capture. The transmethylation reactions will be studied in isolated horizontal cells, and correlated with other known physiological events, such as dopamine-sensitive adenylate cyclase. In RIS-ROS, we will attempt to identify by autoradiography and by subcellular fractionation the intracellular location of the transmethylase enzymes.

Studies from a number of laboratories have suggested that peroxidation of photoreceptor cell lipids is associated with and may be causal in certain types of retinal degenerations. Experiments are proposed to test the hypothesis that lipid peroxidation is a significant factor in photoreceptor degeneration. Three research projects are presented: 1) A number of studies have shown that certain nutrients are essential for normal retinal structure and function. Among these are included selenium, vitamin E, vitamin C, zinc, and taurine. Since some of these nutrients have anti-oxidant properties, we are proposing that essential nutrient deficiency may make animals more susceptible to light damaage. 2) Several retinotoxic agents have been identified: iron, lipid hydroperoxides, lead, and adriamycin. We will determine if these agents are promotors of lipid peroxidation in the retina. 3) We will study the effects of lipid peroxidation on the function of the retina in vitro. A series of quantitative biochemical, electrophysiological, and morphological studies have been designed to address these objectives. Prior to light strett, the normal defense mechanisms of each animal will be evaluated. These include determination of levels of vitamin E, vitamin C, and taurine. Enzymes that protect against peroxidative damage include glutathione peroxidase, glutathione reductase, glutathione S-transferase, catalase, and superoxide dismutase. The steady state levels of lipid hydroperoxides and polyunsaturated fatty acids will also be determined in these membranes. Baseline values for retinal function (determined by electroretinography) and ultrastructure will be established prior to the onset of stress. Other animals will be subjected to constant illumination for periods of time up to five days. Susceptibility to light damage will be determined by the following objective criteria: Increase in lipid hydroperoxides and decrease in polyunsaturated fatty acids in isolated fod outer segment membranes, decrease in amplitudes of the a- and b- waves with electroretinogram or any alteration in threshold or implicit time, and quantitative morphomoetric analysis of drop-out of photoreceptor cells determined by counting outer nuclear layer nuclei as a function of retinal position. Taken together, these quantitative studies on biochemistry, structure, and function of the retina will provide valuable information regarding the effects of lipid peroxidation on retinal degeneration.

Rod outer segments (ROS) contain the highest levels of polyunsaturated fatty acids (PUFA) of any membrane in the body. Many studies have shown that the major PUFA in ROS, docosahexaenoic acid (22:6 omega 3), is important to the normal function of the retina. Dietary deprivation of its essential precursors leads to changes in the electroretinogram (ERG) in rats, primates, and premature human infants; visual acuity in primates; and brightness discrimination learning in rats. Humans, dogs, and cats with inherited retinal degenerations have lower plasma levels of 22:6 omega 3 than controls. Rats with elevated levels of 22:6 omega 3 in their retinas are more susceptible to light damage, while dietary restriction of 22:6 omega 3 or its precursors protects against light damage. Acute light damage causes a loss of 22:6 omega 3 in ROS, suggesting peroxidation of 22:6 omega 3 may be a causal factor in light damage. Clearly, the retinal degeneration that follows intravitreal injection of Fe 2+ is due to peroxidation of 22:6 omega 3. Attempts to alter the 22:6 omega 3 level in rat ROS through dietary deprivation results in only minor changes in levels of 22:6 omega 3, under conditions where most other body organs show dramatic changes. However, rats raised in different levels of cyclic light show large changes in ROS 22:6 omega 3 levels. These unique features of 22:6 omega 3 in the retina, which are discussed throughout the proposal, suggest that this fatty acid is important to the normal structure and function of the retina. Furthermore, the suggestion of a defect in 22:6 omega 3 metabolism in inherited retinal degenerations makes it even more important that the metabolism of this fatty acid be studied. The long-term goal of this research project is to determine the function of 22:6 omega 3 in normal and diseased retinas. The specific aims of this five-year proposal are: 1) to study the role of 22:6 omega 3 in the inherited retinal degenerations in the miniature poodle and Abyssinian cat, 2) to determine the mechanism of conservation of 22:6 omega 3 in the rat retina during essential fatty acid deficiency, 3) to determine the role of 22:6 omega 3 in the biochemical adaptation of the rat retina to cyclic light, as related to susceptibility to acute light damage, as well as to damage by chronic exposure to cyclic light of different intensities, 4) to study the effects of chronic administration of antioxidants on the susceptibility of the retina to damage by acute constant light challenge, as well as to damage by chronic exposure to cyclic light of different intensities, and 5) to determine the site of elongation and desaturation (retinal vs. extraretinal) of 22:6 omega 3 and to study these metabolic processes. To achieve these goals, a series of in vivo and in vitro experiments are proposed in which the metabolism of 22:6 omega 3 will be studied in detail. Each step of the elongation and desaturation pathways in the formation of 22:6 omega 3 will be tested in retinas and liver homogenates of dogs and cats with inherited retinal degeneration. Rats will be raised on omega3- and/or omega6-deficient diets and injected intravitreally with lipid precursors in order to study the biochemical mechanisms of conservation of 22:6 omega 3. Similar groups of animals will be raised in bright or dim cyclic light to determine if elevated dietary PUFA levels make them more susceptible to light damage. The results of these studies will give a better understanding of the metabolism of 22:6 omega 3 in the retina and perhaps shed some light on the role of this fatty acid in retinal degenerations.

Light stimulates the hydrolysis of a phospholipid, phosphatidylinositol 4,5-bisphosphate (PlP2), in vertebrate and invertebrate retinas, which generates two intracellular second messengers. One, 1,4,5-inositol trisphosphate (1,4,5-lP3), a water soluble molecule, interacts with specific intracellular receptors and causes release of bound calcium. The other, 1,2-diacylglycerol (1,2-DG), a lipid molecule, activates protein kinase C (PKC). Five types of PLCs have been described that are specific for the hydrolysis of PIP2. In bovine ROS, PLC activity is activated by arrestin (aka 48K protein and S-antigen). Our long-term goal is to understand the mechanism of generation and the role of PIP2-derived second messengers in the vertebrate retina. The specific aims for the next five years are: 1) to identify the PLC subtypes in the retina by probing with a variety of PLC-specific antibodies, using immunocytochemistry and immunoblots. 2) to characterize the PLCs in the retina and ROS. PLCs will be purified from ROS and the mechanism of activation by arrestin will be determined. Antibodies will be generated against purified PLCs and used to screen expression libraries so that the PLCs can be cloned and their genes sequenced. 3) to localize and identify the inositol phosphate receptors in the retina, using subcellular fractionation and immunocytochemistry. 4) to establish a reconstituted system for study of light-stimulated PIP2 hydrolysis. These studies will utilize biochemical, morphological, immunological, and molecular biological techniques. This expertise is available in the PI's laboratory; however, collaborations with experts in specific areas have been arranged, also. The result of these studies will be more precise information about the role of PIP2 hydrolysis in the retina and rod outer segments. Since this reaction is involved in control of calcium levels in cells, our hypothesis is that it may be involved in adaptation of photoreceptor cells. To date, there are no known genetic defects in the vertebrate visual system involving enzymes of the PIP2 cascade. However, abnormalities in both PLC and PKC in Drosophila eyes are associated with aberrant retinal function and/or retinal degeneration.

Rod outer segments (ROS) contain the highest levels of polyunsaturated fatty acids (PUFA) of any membrane in the body. Many studies have shown that the major PUFA in ROS, docosahexaenoic acid (22:6 omega 3), is important to the normal function of the retina. Dietary deprivation of its essential precursors leads to changes in the electroretinogram (ERG) in rats, primates, and premature human infants; visual acuity in primates; and brightness discrimination learning in rats. Humans, dogs, and cats with inherited retinal degenerations have lower plasma levels of 22:6 omega 3 than controls. Rats with elevated levels of 22:6 omega 3 in their retinas are more susceptible to light damage, while dietary restriction of 22:6 omega 3 or its precursors protects against light damage. Acute light damage causes a loss of 22:6 omega 3 in ROS, suggesting peroxidation of 22:6 omega 3 may be a causal factor in light damage. Clearly, the retinal degeneration that follows intravitreal injection of Fe 2+ is due to peroxidation of 22:6 omega 3. Attempts to alter the 22:6 omega 3 level in rat ROS through dietary deprivation results in only minor changes in levels of 22:6 omega 3, under conditions where most other body organs show dramatic changes. However, rats raised in different levels of cyclic light show large changes in ROS 22:6 omega 3 levels. These unique features of 22:6 omega 3 in the retina, which are discussed throughout the proposal, suggest that this fatty acid is important to the normal structure and function of the retina. Furthermore, the suggestion of a defect in 22:6 omega 3 metabolism in inherited retinal degenerations makes it even more important that the metabolism of this fatty acid be studied. The long-term goal of this research project is to determine the function of 22:6 omega 3 in normal and diseased retinas. The specific aims of this five-year proposal are: 1) to study the role of 22:6 omega 3 in the inherited retinal degenerations in the miniature poodle and Abyssinian cat, 2) to determine the mechanism of conservation of 22:6 omega 3 in the rat retina during essential fatty acid deficiency, 3) to determine the role of 22:6 omega 3 in the biochemical adaptation of the rat retina to cyclic light, as related to susceptibility to acute light damage, as well as to damage by chronic exposure to cyclic light of different intensities, 4) to study the effects of chronic administration of antioxidants on the susceptibility of the retina to damage by acute constant light challenge, as well as to damage by chronic exposure to cyclic light of different intensities, and 5) to determine the site of elongation and desaturation (retinal vs. extraretinal) of 22:6 omega 3 and to study these metabolic processes. To achieve these goals, a series of in vivo and in vitro experiments are proposed in which the metabolism of 22:6 omega 3 will be studied in detail. Each step of the elongation and desaturation pathways in the formation of 22:6 omega 3 will be tested in retinas and liver homogenates of dogs and cats with inherited retinal degeneration. Rats will be raised on omega3- and/or omega6-deficient diets and injected intravitreally with lipid precursors in order to study the biochemical mechanisms of conservation of 22:6 omega 3. Similar groups of animals will be raised in bright or dim cyclic light to determine if elevated dietary PUFA levels make them more susceptible to light damage. The results of these studies will give a better understanding of the metabolism of 22:6 omega 3 in the retina and perhaps shed some light on the role of this fatty acid in retinal degenerations.

DESCRIPTION (Adapted from applicant's abstract): The long-term objective of this research proposal is to define the role of retinal lipids and retinal lipid metabolism in health and disease. This will be carried out using a variety of in vitro and in vivo models. The mechanism of selective enrichment for 22:6n-3 in the retina will be explored in retinal homogenates using labeled glycerol and pulse-chase methods. The question of de novo lipid synthesis versus post-synthesis lipid remodeling will be investigated. In addition, studies not completed during the current funding period will be continued using rats raised in high- and low-intensity light environments. These rats will be challenged with the pro-oxidant ferrous sulfate to determine their relative capabilities to defend their retinas with endogenous antioxidants, which appear to be upregulated by high-intensity light environments. Studies will also be continued that explore the role of 22:6 in inherited retinal disease using the prcd poodle as a model. Particular emphasis will be placed on the possibility that trafficking of 22:6 is abnormal in these dogs based upon the finding that their blood levels are low. Lastly, the pathways for the formation of some 14 carbon fatty acids will be investigated, as well as their incorporation into retinal proteins.

DESCRIPTION (Adapted from applicant's abstract): Activation of a variety of cell surface receptors leads the activation of PLC and the subsequent hydrolysis of plasma membrane phospholipid, phosphatidylinositol bis-phosphate (PIP2). The two products of PIP2 hydrolysis, inositol-3-phosphate (IP3) and diacylglycerol (DAG), are second messengers involved in the regulation of cellular Ca2+ and protein kinase C (PKC) activities. PIP2 is also a substrate of a PI-3 kinase. The product of this PI-3 kinase, phosphatidylinositol tris-phosphate (PIP3), appears to be an important second messenger for a distinct cellular pathway. Vertebrate photoreceptor outer segments contain light-sensitive PLC, PKC, and an active PI-3 kinase. In this proposal, the applicant proposes experiments to define the role of PLC and PI-3 kinase. There are 3 specific aims: (1) identification of the light-sensitive PLC in rod outer segments (ROS) and elucidation of its mechanism of activation; (2) investigation of the enzymes in the PI cycle that replenish PIP2 in photoreceptor; and (3) determination of the role of PI-3 kinase in the retina.

[unreadable] DESCRIPTION (provided by applicant): Support is requested for continuation of our NEI Vision Center Grant at the University of Oklahoma Health Sciences Center (OUHSC). Four Modules are proposed: Image Acquisition and Analysis, Animal Resources, Bioinformatics/Proteomics, and Molecular Biology. These modules provide essential services to 20 NIH-funded investigators with 14 NEI-eligible grants. The Image and Animal Modules are located in the Dean A. McGee Eye Institute (DMEI) in renovated facilities that include 2,000 square feet for the core modules and 12,000 square feet for research laboratories. The latter two are located in the Biomedical Sciences Building (BMSB) in newly renovated space in the Departments of Cell Biology and Biochemistry & Molecular Biology. All modules and research laboratories are within three blocks of each other. Since the last submission, 9 NEI-funded investigators have been recruited into the Departments of Ophthalmology and Cell Biology. The availability of core support is a major contributor to our rapid growth. These four core modules will increase productivity of the vision research activities at the OUHSC by providing stable, centralized services with core personnel. The modules will promote and enhance funded projects by providing resources that allow multidisciplinary approaches; facilitate the initiation of pilot studies; promote collaborative research projects between investigators; aid in the recruitment of other vision researchers to the OUHSC; provide opportunities for researchers on campus to initiate vision research projects, in collaboration with vision Core Center investigators; and provide resources for graduate students [unreadable] and postdoctoral fellows in vision research laboratories. Institutional support from the provost, DMEI, and the Departments of Ophthalmology and Cell Biology will provide laboratory space; funds for renovation of laboratory space; partial support for core modules, including matching funds for new instruments and core personnel salaries; partial support for faculty salaries; and salaries and start-up funds for the recruitment of 2 new faculty members over the next 4 years. This broad-based institutional support will ensure that each Core Module is staffed and supplied to completely serve the needs of vision researchers at the OUHSC. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (Applicant?s Abstract) The primary goal of the forthcoming X International Symposium on Retinal Degenerations, a satellite meeting of the XV International Congress of Eye Research, is to promote the exchange of current information and ideas amongst basic and clinical scientists in the interest of fostering new advances in our understanding of basic mechanisms and the development of therapeutic interventions in acquired and inherited retinal degenerations. Special effort has been made to introduce new investigators into the field and to include established investigators with clinical and basic science backgrounds. We have reached a point in the history of scientific endeavor at which there is common interest among basic and clinical scientists in understanding the fundamental mechanisms underlying retinal diseases. This meeting, which has been held biennially since 1984, has been responsible for fostering many of the collaborative research projects that have provided vital new information. As with previous meetings, the 2002 conference will feature a rich mixture of investigators, ranging from cell and developmental biologists to clinician-scientists from major research/clinical centers throughout the world. The 2002 meeting will be held in Antalya, Turkey on Sept. 29 - Oct. 5, 2002 as a satellite meeting of the XV International Congress of Eye Research to be held in Jerusalem from Oct. 6 - 11. The meeting will have eight sessions of paper presentations and dedicated time for poster discussion. The program will be finalized 3-4 months before the meeting and will include the very latest information. Topics covered in previous meetings include new genes and loci, gene therapy, macular degeneration, animal models, medical therapies, mechanisms of cell death, transplantation, and retinal prostheses. A highly favorable aspect of the nine meetings held to date is the intimate environments that have provided for formal and informal discussions among established scientists with diverse backgrounds. This relaxed atmosphere has allowed clinicians and researchers from all parts of the to meet each other and learn of each other?s work. From the first meeting held in 1984, we have encouraged young persons to attend. Beginning in 2000, we supported the attendance of eleven students, postdoctoral fellows, and young scientists new to the field, who had the opportunity to meet and interact with established scientists. This is a key feature that distinguishes the International Symposium on Retinal Degenerations from other scientific meetings.

DESCRIPTION (provided by applicant): The overall objectives for the second five years of our COBRE program are to continue to improve the quality and quantity of VISION RESEARCH at the University of Oklahoma Hearth Sciences Center (OUHSC), to increase the long-term acquisition of NIH competitive funding in Oklahoma through the mentoring of project investigators and early career investigators (ECls), to recruit senior investigators to the OUHSC, and to develop support for the infrastructure of our vision research programs. This program is strongly supported by the leadership of the OUHSC and the Dean A. McGee Eye Institute (DMEI). The specific aims of this COBRE renewal application are: A. To strengthen and to augment institutional biomedical research capabilities in vision research through the mentoring of project investigators by experienced, dedicated senior investigators. B. To broaden the research and mentoring capabilities of early career investigators by providing support for a second research project. C. To increase the critical mass of vision researchers at the OUHSC by recruiting four vision investigators. D. To enhance the infrastructure critical for expanding vision research in Oklahoma. E. To continue to foster collegial and collaborative relationships between COBRE investigators and other scientists. F. To oversee outcome milestones and expectations that will ensure the success of the COBRE program. G. To develop and implement an "exit strategy" that will ensure continuity of the COBRE initiatives after the second 5 years of COBRE support.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This supplemental application requests funding for equipment to establish a Core Module in Functional Genomics, which has three interrelated components that will be used extensively by the PJIs and related research projects. The three components of the Functional Genomics Module are: 1) A facility that will be used to test gene function in genetically modified mice. We will create a state-of-the-art mouse genetics facility, which will mainly support the manipulation of the mouse genome by targeted mutagenesis in mouse embryonic stem cells. This facility will allow us to generate animal models of human diseases and pathology through precise genomic modifications in mouse embryonic stem cells. 2) An in vitro facility for reverse genetics using RNA interference in cell culture. RNAi, the introduction of sequence-specific double-stranded small inhibiting RNAs (siRNAs), has become a powerful tool to knock down gene expression in isolated cells, siRNAs can be introduced into retinal neurons grown in a chemically defined environment to study the function of numerous genes. The inhibition of the expression of endogenous and transfected genes using in vitro systems can be evaluated free from the homeostatic influence of the whole organism. 3) An in vivo facility for reverse genetics using RNA interference in animal models. The therapeutic potential of iRNA will be investigated by long-term expression of the siRNA molecules in the terminally differentiated cells of the intact retina. Funds are requested for equipment only; no funds are requested for A&R. Successful implementation of this Functional Genomics Module will shorten the time for submission of first-time R01 applications by our 5 COBRE-funded promising junior investigators, and expand the research horizons for 15 other vision researchers, module directors, and/or COBRE mentors on our campus. [unreadable] [unreadable]

role model; health science research; vision; biomedical facility;

Project Summary/Abstract This application is a request for funds to support the travel of young investigators to attend the XVIIIth International Symposium on Retinal Degeneration (RD2018) to be held in Killarney, Ireland on September 3-8, 2018. This meeting is a satellite of the XXIIIth Biennial Meeting of the International Society for Eye Research (ISER), to be held in Belfast, Northern Ireland, UK September 9-12, 2018. Since the first RD meeting in 1984, we have focused on macular degeneration and inherited retinal degenerations that affect photoreceptors and the retinal pigment epithelium. The Specific Aims of the XVIIIth International Symposium on Retinal Degeneration are: 1. To enhance the emerging careers of 20 Young Investigators (including women and minorities) in retinal degeneration research by providing full travel support. 2. To provide a platform to advance career development of Young Investigators. 3. To provide a forum for dissemination of the most recent advances in the state of knowledge on the pathophysiologic mechanisms of acquired, inherited, and age-related retinal degenerations, and new therapeutic approaches to these diseases. 4. To create an environment that will facilitate the exchange of novel ideas among basic and clinician scientists and generate the opportunity for vision scientists of all ethnic groups and social backgrounds to meet and establish research collaborations.

The goals of this proposal are to create, manage and maintain core facilities that will provide technical support, equipment access and personnel training for supported modules. We will establish two core modules including Live Animal Imaging and Functional Analysis, and Cellular Imaging and Morphometric Analysis Modules. These modules will be housed in convenient central locations, each containing state-of-the-art resources operated by highly qualified and well trained technicians that are supervised by junior faculty level Systems Managers and experienced senior vision researchers. The availability of multiple types of advanced equipment, sophisticated software, and hands on training will dramatically increase the quality and quantity of research achievements by the users of our Vision Core Grant facilities. Successful operation of these core facilities will: 1) increase opportunities for rigorous translational research using clinically relevant and non-invasive imaging procedures, 2) generate more collaborative projects that require multiple areas of expertise, 3) increase and enhance productivity of existing research projects thereby allowing participating investigators to remain competitive for funding, 4) promote recruitment of additional faculty, including two clinician scientists whom we are currently interviewing and 5) support the development of new research strategies based on the acquisition of data from the use of equipment previously unavailable to the PI's.

DESCRIPTION (provided by applicant): Our lab was the first to discover that ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for biosynthesis of very long chain (VLC; eC26) fatty acids that are found as components of more complex lipid molecules such as sphingolipids and phosphatidylcholine. ELOVL4 synthesizes the VLC polyunsaturated fatty acids (VLC-PUFA) found in retina and testes, and VLC saturated fatty acids (VLC-FA) in skin and brain. Heterozygous inheritance of mutant ELOVL4, which lacks the ability to synthesize these fatty acids, causes juvenile macular degeneration in autosomal dominant Stargardt's macular dystrophy (STGD3). Humans with homozygous inheritance of the STGD3 mutation (ELOVL4 mutant/mutant), and thus make no VLC- PUFA/VLC-FA, develop ichthyosis, seizures, intellectual disability, and spastic quadriplegia, and die within the first few years of ife. This establishes a causal link between the mutation in ELOVL4 to a neurodegenerative disease; other than that, nothing is known about the role and importance of VLC-FA in the brain. Our group showed that VLC-FA are in sphingolipids in the rat brain. We have successfully generated an animal model that recapitulates the human condition. This unique animal model will enable us to study the role of ELOVL4 and VLC-FA in neural cell development, structure and function, which is a novel and unexplored area of research. Our central hypothesis is that VLC-FA play an important role in the development/maintenance of as yet undescribed activities in the CNS and that mutations in ELOVL4 and/or loss of VLC-FA lead to impaired neural function, evident by hyper-excitability and seizures. This novel hypothesis and the studies proposed herein to test it will allow us to break new ground in understanding neural development and the biological role of ELOVL4 and its VLC-FA products in the brain. We propose the following three specific aims to test our hypothesis. In this R21 application, we propose a series of experiments that will provide us with the basic information we will need to submit an R01 application in the second year. 1. To test the hypothesis that a loss of VLC-FA within the CNS is sufficient to cause impaired neural development leading to neural dysfunction and seizures. 2. To characterize the expression pattern of ELOVL4 and its products within the CNS. 3. To determine the mechanism of neural dysfunction mediated by mutations in ELOVL4 and/or loss of VLC-FA.

ABSTRACT Administrative Core The Administrative Core is responsible for all administrative and oversight activities related to the Vision Core grant. This includes providing administrative support for core facilities and equipment to NEI R01-funded and other vision researchers and their laboratory members; preparing and submitting all required reports to the National Eye Institute; arranging all meetings related to any aspect of administration of the Vision Core grant; handling all financial matters related to the vision core grant, including purchasing of supplies for each core, making sure that all service contracts are paid in a timely manner, preparing monthly financial reports for each core, and billing monthly on behalf of the Cellular Imaging Core; and liaising with the administration of the OUHSC on all matters relevant to the successful operation of the Vision Core grant.

There have been impressive advances in understanding the molecular and cellular mechanisms of aging, including the discovery of manipulations that delay aging and increase healthspan. Importantly, these interventions also reduce or prevent age-related diseases. These outcomes raise the possibility that multiple human diseases arise from a common cause ? aging. The premise of this CoBRE Phase 1 is that the mechanisms of aging and the mechanisms of age-related diseases share common cellular and molecular processes that underlie healthspan and lifespan. An important corollary to this concept is that pre-clinical and clinical research on age-related diseases must incorporate an understanding of the cellular/molecular changes that occur with age in order to adequately develop treatments for age-related diseases. Here, we propose a multidisciplinary, inter-departmental, and inter-institutional CoBRE program focused on Cellular and Molecular Geroscience. Geroscience is a new, interdisciplinary scientific field that addresses the cellular and molecular events that dramatically increase the risk for disease with age, create a ?permissive milieu? and, as a result, disease increases exponentially. Our program has exceptional institutional support. The program is highly innovative in that it combines mentoring of promising junior investigators (PJIs) by outstanding scientific experts who are currently studying mechanisms of aging and by faculty investigating age-related disease in a manner that will increase both the quantity and quality of on-going disease-related research in the context of the aging organism. These goals will be accomplished through the mentoring of PJIs, who have faculty appointments at OUHSC; recruiting senior investigators to the OUHSC campus; and developing the necessary infrastructure for support of the research program. The specific aims for the program are: 1. Develop and expand institutional biomedical research in Geroscience through the mentoring of PJIs by highly experienced, dedicated senior investigators. 2. Enhance the infrastructure critical for expanding Geroscience research in Oklahoma. 3. Foster collegial and collaborative relationships between CoBRE investigators and other scientists. 4. Establish milestones and expectations that ensure the success of the program and its participants. The outcome will be a sustainable, interdisciplinary research structure on the OUHSC campus, which will produce a new generation of collaborative Geroscience-trained researchers and establish OUHSC as a leader in Geroscience.

No abstract provided