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High-probability grants
According to our matching algorithm, Yiannis Koutalos is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
1997 — 2001 |
Koutalos, Yiannis |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Phototransduction in Cone Photoreceptors @ University of Colorado Denver
The long-term goal of this research is the understanding of the biochemical processes underlying light transduction in cone photoreceptors, the retinal cells responsible for seeing at high light intensities. The most extensively studied photoreceptors are the rods, which are responsible for seeing at low light intensities. Both rods and cones utilize cyclic GMP (cGMP) as the internal transmitter that mediates the conversion of light into an electrical signal. Compared to rods, cones are less sensitive and respond faster to light. These differences are thought to be due to differences in the enzymatic machinery of the two cell types, although specific information is lacking for the cone photoreceptor enzymes. This project will employ electrophysiological methods to characterize the activities of the cGMP-metabolizing enzymes in single cone outer segments. The specific aims are: (1) Characterization of the cGMP-activated channels. (2) Characterization of the guanylate cyclase, the enzyme producing cGMP. (3) Characterization of the phosphodiesterase, the light-sensitive enzyme hydrolyzing cGMP. The significance of the project lies in the characterization of the biochemical processes that underlie the ability of cones to function at high light intensities. The proposed electrophysiological approach is almost unique for the successful pursuit of its objectives, since the limited availability of retinas rich in cone outer segments has hindered biochemical studies of the cone phototransduction machinery. The quantitative understanding of the biochemical basis of the visual transduction process in cones will significantly improve our knowledge of the physiology of the retina. Such knowledge will contribute to our understanding of retinal degeneration diseases, especially cone-related ones, like cone dystrophies.
|
0.943 |
2004 — 2021 |
Koutalos, Yiannis |
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. |
Transport Processes in Photoreceptors @ Medical University of South Carolina
ABSTRACT During the previous grant period we showed that 11-cis retinal, the light-detecting chromophore of the visual pigment, is the primary source of the toxic deposits that accumulate in the Retinal Pigment Epithelium (RPE) as lipofuscin in the human retina. We also showed that central RPE, the area underlying the macula, contains low levels of these toxic deposits. Defects of retinoid processing have long been linked to diseases of the retina, and the pivotal role played by 11-cis retinal as a mediator of acute and long-term damage suggests specific points in the processing pathway as potential therapeutic targets. In the previous funding period we focused exclusively on rods, which comprise more than 90% of the photoreceptor cells of the human retina. Here, we shift our attention to cone photoreceptors, which are the ones supporting vision for most of our daily activities, and are concentrated in the macula, the part of the retina responsible for high acuity vision. Both the 11-cis and all-trans isomers of retinal are highly reactive aldehydes and photosensitizers, and their reactions with photoreceptor components give rise to the toxic deposits that accumulate in the RPE in the form of lipofuscin. In contrast to rods, which use 11-cis retinal, cones use 11-cis retinol as the source for their visual pigment chromophore. 11-Cis retinol is oxidized to 11-cis retinal within the cell and is far less toxic than either 11-cis or all-trans retinal. We will determine and compare the damage mediated by all-trans retinal, 11- cis retinal and 11-cis retinol in single living cone photoreceptors isolated from monkey and human donor eyes. We will use fluorescence imaging of single photoreceptors to measure oxidative damage and the formation of lipofuscin fluorophore precursors. The aims of the research are: Specific Aim #1: Determine the damage-causing potential of all-trans retinal in cone outer segments. Specific Aim #2: Determine the damage-causing potential of 11-cis retinal in cone outer segments. Specific Aim #3: Determine the damage-causing potential of 11-cis retinol in cone outer segments. Results from these studies will provide new insights into the basic pathogenic mechanisms operating in the macula and underlying vision loss in diseases like Age-related Macular Degeneration (AMD). They will investigate the specialized mechanisms employed by cone photoreceptors to protect the macula from retinaldehyde toxicity. They will allow the evaluation of the potential toxicity of therapies for visual pigment chromophore deficiencies that depend on boosting the chromophore supply; they will also provide a measure for the expected effectiveness of the opposite type of therapies, which aim to limit lipofuscin formation by slowing down the generation of 11-cis retinal.
|
1 |
2015 — 2016 |
Koutalos, Yiannis |
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.) |
Novel Assay of Human Photoreceptor Cell Metabolism @ Medical University of South Carolina
? DESCRIPTION (provided by applicant): The death of retinal photoreceptor cells is one of the primary causes of vision loss. Substantial loss of photoreceptors occurs with age in normal human eyes, and is significantly exacerbated in Age-related Macular Degeneration (AMD), a leading cause of blindness in the United States. Photoreceptor cell death is also the cause of vision loss in several inherited retinal degeneration diseases, such as Retinitis Pigmentosa. Robust metabolic activity is necessary for cells to support their physiological functions and maintain their viability. Metabolic defects that result in deterioration of metabolic competence underlie a variety of degenerative diseases including retinal degenerations. Thus, treatments that protect or enhance the metabolic competence of photoreceptors may have significant therapeutic potential. Currently, there is no assay for testing the beneficial or possibly deleterious effects of potential treatments on human photoreceptor cells. We propose to establish a novel assay for measuring the metabolic competence of human photoreceptors. The assay uses single living rod photoreceptors isolated from defined regions of the human retina. The eyes and retinas will be clinically evaluated and rod photoreceptor cells will be isolated from retinas free of disease. Metabolic competence will be measured from the conversion of supplied all-trans retinal to retinol, a reaction that requires NADPH and the cell is equipped to carry out as part of its light-detecting function. The capacity of a cell to generate NADPH will be estimated from the fraction of all-trans retinal converted to retinol, which can be directly measured with fluorescence imaging from the intrinsic retinoid fluorescence. The proposed experiments will provide the first measurements of human rod photoreceptor metabolism and its variation across the retina. They will also establish the baseline parameters for the future use of the assay in the evaluation of proposed treatments for retinal degenerations. The aims of the research are: Specific Aim #1: Determine the dependence of the metabolic competence of human rod photoreceptors on the type and concentration of metabolic substrate. Specific Aim #2: Determine the spatial dependence of the metabolic competence of human rod photoreceptors across the retina. The research will establish an assay for testing the efficacy of therapeutic approaches at the single human photoreceptor cell level. It will determine the relation between the clinical assessment of a retina free of disease and the metabolic competence of individual photoreceptor cells isolated from that retina. The assay will be a valuable tool in the development of treatments that aim to improve human photoreceptor metabolic competence and thereby extend their lifespan. Such information will play a key role for the treatment of retinal degeneration diseases including AMD and Retinitis Pigmentosa.
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1 |