1986 — 1987 |
Peachey, Neal S |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Oscillatory Potentials in Retinal Disease @ University of Illinois At Chicago |
0.936 |
2003 — 2005 |
Peachey, Neal S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Mouse Dc-Electroretinogram @ Cleveland Clinic Lerner Col/Med-Cwru
DESCRIPTION (provided by applicant): The retinal pigment epithelium (RPE) is critically involved in many functions required for normal retinal function including the flow of nutrients and waste products between the photoreceptors and the choroidal circulation, the visual cycle, and the phagocytosis of shed outer segment disks. In addition, mutations in RPE-specific genes have been implicated in a wide range of hereditary retinal disease, and this information is being used to develop corresponding mouse models. In the present project, the focus is on the electrical responses generated by the RPE in response to activity of the neural retina. While specific aspects of RPE function may be studied using the electroretinogram (ERG) recorded using dc-coupled amplification, this has not been applied to the mouse. Moreover, fundamental questions remain regarding the origin of the different components of the dc-ERG. In Aim 1, we will study normal wild-type mice, to define the stimulus-response characteristics of the mouse dc-ERG, and the time course over which these develop. In Aim 2, we will test the hypothesis that the mouse dc-ERG is initiated primarily by rod photoreceptor activity, using KO lines for transducin and rhodopsin, and mutants in which the cone population is increased (rd7) or decreased (comas transgenic). In Aim 3, we will use Kir4.1 KO mice to test the hypothesis that this channel is involved in c-wave generation. In Aim 4, we will use cftr KO mice and adenoviral delivery of CFTR constructs to test the hypothesis that the fast oscillation is generated by CFTR activity. In Aim 5, we will use dc-ERG recordings to study the relationship between photoreceptor degeneration and changes in RPE function. First, we will examine how A2E accumulation in abcr-mutant mice alters RPE function. Next, we will test the hypothesis that functional RPE abnormalities occur at early stages using three lines of mice with similar rates of photoreceptor degeneration. In two, the primary defect resides in the photoreceptors (rds/+ and Bouse transgenic mice). In vitilligo mice, a similar rate of photoreceptor degeneration is induced by defect in the RPE. At the completion of this project, we expect to have defined an optimal means for recording the mouse dc-ERG in vivo, to have a thorough understanding of the processes that underlie the different components of the dc-ERG, and a more complete understanding of how these components are affected by disorders of the outer retina.
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0.913 |
2011 — 2012 |
Gregg, Ronald G (co-PI) [⬀] Peachey, Neal S |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mouse Model of Dbc Dysfunction @ Cleveland Clinic Lerner Com-Cwru
DESCRIPTION (provided by applicant): Congenital stationary night blindness (CSNB) is the clinical term for non-progressive retinal disorders that impair rod-mediated vision. The complete form of CSNB (cCSNB) is caused by defects in depolarizing bipolar cell (DBC) signal transduction and in patients has been linked to mutations in NYX, GRM6 or TRPM1. Because the flow of all visual input is transferred from the outer to the inner retina via bipolar cells, it is critical to understand the mechanism of signal transduction in DBCs. Recent work has defined several, but not all, players in this cascade. In this project, we will identify another key protein. In Aim 1, we will identify the gene and mutation that underlies a new mouse model of DBC dysfunction, nob5. The nob5 gene locus is distinct from all other known models of DBC dysfunction and therefore its identification will add another protein to those known to be critical for DBC function. These studies will use next generation sequencing and positional cloning to map and clone the gene responsible for the nob5 phenotype. In Aim 2, we will define the nob5 phenotype with respect to retinal function, using electroretinography and whole-cell patch clamp recordings from rod and cone DBCs and cone hyperpolarizing bipolar cells, and the morphology of the synapses between photoreceptors and DBCs, using confocal microscopy and immunohistochemistry. At the completion of this project, we will have identified a new protein that is required for normal DBC function and which can be used to screen patients with cCSNB. PUBLIC HEALTH RELEVANCE: This project will make detailed studies of a new mouse model (nob5) that lacks depolarizing bipolar cell (DBC) function. The nob5 gene has not been identified, but is known to involve a protein that has not been previously implicated in DBC function. Identification of the nob5 gene will expand our understanding of DBC signal transduction and will identify a potential new candidate gene for the complete form of human congenital stationary night blindness.
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0.912 |
2019 — 2021 |
Mcanany, James Jason (co-PI) [⬀] Peachey, Neal S. Sagdullaev, Botir T. (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Vision Loss in X-Linked Juvenile Retinoschisis @ Cleveland Clinic Lerner Com-Cwru
Abstract X-linked retinoschisis (XLRS), the most common cause of juvenile onset retinal degeneration in males, is characterized by cystic-appearing retinal lesions and early visual deficit. XLRS is caused by mutations in the RS1 gene that encodes the protein retinoschisin (RS1), which is expressed panretinally. Changes in retinal structure and function observed in young XLRS patients and Rs1 KO mice raise new questions regarding the role of RS1 in early XLRS pathophysiology that may impact the severity of the disease in adulthood. Questions motivated by our preliminary findings that concern the nature and extent of visual deficits in XLRS, as well as the sites and mechanisms of disease action, will be addressed in the following 3 Specific Aims. In Aims 1 and 2 we will use three Rs1 mutant mouse models, with differing levels of disease severity, to identify early retinal maladaptive changes and abnormalities associated with XLRS. In addition to a KO for Rs1, we are working with two novel ?humanized? mouse models that carry human disease causing Rs1 point mutations (C59S, R141C) chosen because of their distinct impacts on RS1 structure and function. In Aim 1, we will define early changes in XLRS retinal structure and function using electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and immunohistochemistry. Aim 2 will determine the impact of aberrant retinal function on visual discrimination and how it differs among the animal models. We then assess visually driven behavior in living mice, to determine functional metrics such as contrast sensitivity and visual acuity that are translatable to the human subjects studied in Aim 3. Together, Aims 1 and 2 will test the hypothesis that the visual deficits are directly related to early structural changes and will identify the cell type(s) that are critical to define this relationship. In Aim 3, we will use psychophysical assays to define the mechanisms that contribute to visual impairment in XLRS patients. These analyses will test the hypothesis that mutant RS1 results in behavioral abnormalities akin to those observed in the Rs1 mouse models, including reduced contrast sensitivity, elevated internal noise levels, and summation abnormalities. We anticipate the pattern of visual abnormalities to be consistent with disrupted visual maturation, as seen in other early onset retinal conditions. The completion of these Aims will greatly expand our understanding of the time course and impact of Rs1 mutations on the retina, will define the cellular basis for visual function loss in XLRS patients and will identify new therapeutic targets and outcome measures that may be more suitable for evaluating experimental therapies than SD-OCT and ERG analysis. Our findings will advance the general understanding of XLRS and how we approach and design trials of experimental therapy.
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0.912 |