2009 — 2013 |
Mcanany, James Jason |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Mechanisms Limiting Visual Performance in Retinal Degenerations @ University of Illinois At Chicago
DESCRIPTION (provided by applicant): Retinal degenerative diseases are the leading cause of unbeatable blindness in the industrialized world. Individuals with retinitis pigmentosa (RP), one of the most frequently occurring blinding hereditary retinal dystrophies, can have profound spatial contrast sensitivity (CS) deficits of unknown origin. Because contrast processing forms the basis for form, motion, and depth perception, evaluation of CS can provide a sensitive assessment of visual performance deficits. However, CS tests have potentially serious limitations in their current form, and the paucity of information regarding the factors underlying CS deficits is a fundamental impediment to developing better testing strategies. The goals of this award are to: 1) provide the applicant with clinical skills and a fundamental knowledge of ocular diseases;2) apply this knowledge to develop an innovative testing strategy for identifying the mechanisms underlying CS losses in persons with RP. During the mentored phase, the applicant will master clinical vision testing methods, such as electroretinography and retinal imaging, while conducting mentored research. This phase will culminate in the applicant securing a tenure-track faculty position and developing a laboratory focused on determining the relationship between retinal pathophysiology and visual dysfunction. The independent phase will focus on two specific research aims: Aim 1 is to develop an optimized visual-noise-based testing strategy for evaluating letter CS that is not subject to the limitations of current tests. Noise-based techniques provide more information than standard tests because performance is factored into three independent underlying mechanisms: both additive and multiplicative noise within the visual pathway, and the ability to extract the signal from the noise. However, several issues regarding noise-based tests have been identified in pilot work, and these issues must be resolved to establish an optimized test. Aim 2 will apply the optimized testing strategy to persons with RP to identify the factors underlying CS losses. It has been suggested that high levels of additive noise underlie CS deficits in individuals with RP, but empirical data have not been obtained to evaluate this hypothesis
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1.009 |
2016 — 2021 |
Mcanany, James Jason |
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 Early Functional Loss in Diabetic Eye Disease @ University of Illinois At Chicago
? DESCRIPTION (provided by applicant): There is mounting evidence that diabetes mellitus affects retinal neurons before abnormalities of the retinal vasculature are apparent clinically. However, relatively little is known about these neural deficits and how they affect visual function in diabetic patients who have minimal or no clinically-apparent diabetic retinopathy (M/N DR). The objective of this proposal is to develop and apply novel approaches for characterizing the nature and extent of visual dysfunction and its potential relationship to neural processes in M/N DR patients. Achieving this objective will provide important new insight into neural dysfunction in patients who have M/N DR and will establish new tests that are capable of classifying patients who have not yet developed clinically- apparent retinopathy, a group that cannot be staged or subtyped according to standard scales. This new insight and the ability to subtype these patients would be of great use in clinical trials that aim to slow or prevent neurodegeneration. Three complementary aims are proposed that use imaging, psychophysical, and electrophysiological techniques to provide new views of retinal function and structure in M/N DR patients and to address important questions generated by our preliminary investigations: Aim 1 will determine the relationship between contrast sensitivity deficits and retinal structure in M/N DR patients by simultaneously acquiring microperimetric contrast sensitivity measurements and optical coherence tomography measurements. Aim 2 will identify the mechanisms underlying electrophysiological abnormalities in these patients by measuring the electroretinogram (ERG) using standard full-field brief flashes of light, contrast- modulated sinewave flicker, focal maculr ERGs, and multi-focal ERGs. This comprehensive battery of electrophysiological tests will be used to challenge common assumptions regarding the sites of disease action that underlie ERG abnormalities. Aim 3 will measure and model contrast sensitivity deficits in diabetic patients who have M/N DR using a visual-luminance-noise-based paradigm that will provide insight into sites and mechanisms of disease action. After accomplishing these aims, we will have: 1) established clinically-applicable approaches to vision assessment that can quantify neural abnormalities in diabetic patients who have M/N DR; 2) gained new insight into the sites and mechanisms that underlie impairments in visual function in these patients. This line of study is particularly important and timely as new therapeutic approaches for treating early- stage retinopathy are being investigated, but the tools that are currently available to subtype patients and evaluate therapeutic efficacy lag behind.
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1.009 |
2019 — 2021 |
Mcanany, James Jason 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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0.923 |