Grant Application Notes 2022

Research (5)

Institution

 

OSU Optometry

PI:  Jeffrey J. Walline, OD PhD

 

Plan a randomized clinical trial (RCT) to determine whether low-concentration atropine can delay the onset of myopia We will randomly assign 70 pre-myopic (pre-nearsighted) children at 14 clinical centers in North America to one month of nightly administration of 0.01%, 0.03%, or 0.05% atropine to determine the strongest dose that pre-myopic children can handle and the proportion of nights they will take eye drops over one month. These data are crucial for a future randomized clinical trial application to the National Eye Institute to determine whether low concentration atropine eye drops can delay myopia onset.

OSU Ophthalmology

PI:  Colleen Cebulla, Shigeo Tamiya & Thomas Mendel

Genetic, neurodegenerative, and proliferative mechanisms in retinal damage and ocular tumors, and potential for therapy

We have identified important inflammatory proteins that contribute to damage that occurs in retinal detachment (RD), a prevalent condition that frequently results in loss of reading vision. Visual loss results from photoreceptor degeneration as well as scarring, which alters retinal structure and function. In addition, patients may develop a form of scarring called epiretinal membrane. There are currently no effective pharmacologic treatments for these diseases. Our long-term goal is to develop neuroprotective and anti-fibrotic therapies to prevent visual loss from RD and other damaging retinal conditions, such as age-related macular degeneration and inherited retinal degenerations. This proposal will evaluate underlying cellular, genetic, and protein changes providing the basis for neurodegeneration and retinal scarring, with a future goal to identify proteins that can be effectively targeted by therapy. This project will also make advances towards developing new and improved gene therapy options for inherited retinal degenerations. 

U of Cincinnati

PI: Winston Kao

Roles of TGFβ Receptors in Cornea Morphogenesis And Homeostasis

Transforming growth factor β (TGF-β) is a pleiotropic cytokine that plays important roles in morphogenesis during embryonic development, maintenance of tissue homeostasis in adult and pathogenesis, e.g., wound healing, angiogenesis, immune anomaly and tumorigenesis, etc. However, its roles in cornea morphogenesis during development and homeostasis in adults remains elusive, because systemic ablation of members of TGF β signaling cascades is often embryonic lethal. To fill these gaps, we have created three novel moues models: KerartTA/tetO-Cre/TgfbR2f/f (KR/TC/Tbr2f/f), KR/TC/Tbr1(Alk5)f/f and KR/TC/Smad4f/f in which the  floxed alleles are ablated in cornea stromal keratocytes upon doxycycline induction and lead to the loss of Tbr2 (Tbr2CK∆/∆), Alk5 (Alk5CK∆/∆) and Samd4 (Smad4CK∆/∆) in cornea keratocytes, respectively. Interestingly, the ablation of such genes during embryonic development severely compromises cornea morphogenesis with ruptured corneas in newborn Tbr2CK∆/∆ and Alk5CK∆/∆ and very thin stroma of Smad4CK∆/∆ in newborn pups, respectively,(XCK∆/∆: Xf/f gene alleles of interest deleted in corneal keratocytes). In contrast, postnatal doxy induction from P21 through P42 leads to pathology resembling keratoconus in Alk5CK∆/∆ mice and keratoglobus in Tbr2CK∆/∆ mice. In further studies, these novel compound transgenic mouse lines will be used to further examine the molecular and cellular mechanisms by which TGFβ receptors signaling in cornea morphogenesis during development and maintenance of cornea functions in adults. Relevance: The prosed studies will yield useful information for a better understanding of regulatory mechanisms of TGF β signaling in the maintenance of corneal health and pathology of corneal diseases at molecular and cellular levels, and design effective treatment regimens of corneal diseases.

Nationwide Children’s Hospital

PI: Hilliary Inger, MD

 

Quantification of axial anisometropia amongst patients with ≥1D spherical equivalent difference in cycloplegic refraction

     Amblyopia is defined as decreased vision in one or both eyes and is caused by poor vision development in childhood. Amblyopia occurs commonly when the prescription in one eye is stronger than the other. There are a variety of factors that influence the power of the ocular prescription, but the length of the eye is known to play a key role. If a child has two eyes whose lengths are different and it causes the prescriptions between the two eyes to be significantly different, it can contribute to the development of amblyopia and poor vision in one eye.

     Atropine is an eye drop that has been shown to slow down the elongation of the eye and may be able to be used to help even out the difference in ocular length if given over a period of time. If the lengths of the eyes can be equalized through the use of this medication, it may help reduce the development of amblyopia and make amblyopia easier to treat in patients with prescriptions that are different between the two eyes.

     Since amblyopia is a condition that can start to develop in early childhood, we need to identify the number of people who may benefit from such a treatment. The proposed project aims to identify how many patients have a difference in the length of their eyes that may be putting them at risk for amblyopia. This information would then identify patients who may benefit from a treatment to reduce the difference in axial length between their eyes to help prevent the development of and improve treatment outcomes for amblyopia.

CWRU

PI: Paul Park

Characterizing photoreceptor cell membranes by atomic force microscopy

Rhodopsin is the light receptor in rod photoreceptors cells that initiate vision via phototransduction upon stimulation by light. Phototransduction is a fundamental biological process involving a set of biochemical reactions in photoreceptor cells. Rhodopsin plays a central role in phototransduction as the initiator of signaling and also plays an important role in maintaining the health of photoreceptor cells. The rhodopsin gene is a hot spot for mutations causing inherited retinal diseases such as retinitis pigmentosa (RP) and congenital stationary night blindness, which currently have no cure or effective treatment. Despite the wealth of knowledge available for rhodopsin, gaps in our structural and molecular understanding of the receptor still exist and a mechanistic description on the effect of mutations in the light receptor causing vision disorders is incomplete. We examine here one aspect of rhodopsin structure that has been understudied because appropriate methodologies have not been available until relatively recently. We will utilize our method we developed using atomic force microscopy to visual rhodopsin organization in the membranes of native retinal tissue. Rhodopsin forms a supramolecular structure at its site of action in the rod outer segment of photoreceptor cells to carry out its function under scotopic conditions. We will examine by atomic force microscopy the dynamics of this supramolecular structure and determine the impact of a diseased state on this membrane organization. Results from our studies will lead to a more accurate mechanistic framework to understand the function of the system under normal conditions and dysfunctions in inherited retinal diseases, which will provide new avenues for scientific inquiry. The long-term impact in studying fundamental aspects of rhodopsin structure and function will be the potential for targeted therapeutics and discovery of novel drug targets.

Bryan grants (2)

Institution

 

OSU Ophthalmology

PI: Cynthia Roberts, Yanhui Ma & Matthew Ohr

Corneal Biomechanics in Diabetes with and without Diabetic Retinopathy

Diabetes is associated with high blood sugar and may lead to the development of Diabetic Retinopathy, which is associated with severe vision loss.  In addition, high blood sugar is also associated with a stiffer cornea.  Therefore, it is proposed to biomechanically characterize the cornea and scleral response of diabetic subjects with retinopathy and compare them to both those without retinopathy as well as normal subjects in a separate study.  A clinical device which uses high-speed imaging during corneal deformation with an air puff will be used to generate a set of dynamic corneal response parameters.  In addition, a device which captures the pattern of vessels in the retina will be used to compare the biomechanical data to the retinal vascular data.  Once this dataset of deformation parameters and vascular parameters is generated, statistical analysis will be used to develop a biomechanical biomarker.  Subjects will all be contacted at 5 years from their first baseline visit to obtain longitudinal data that might be used to predict the risk of progression in diabetic retinopathy.  

OSU Optometry

PI: Heather Chandler, PhD

Novel vitreous replacement for diabetic retinopathy

The vitreous humor is an avascular gel that is responsible for delivering antioxidants to ocular tissues and maintaining an oxygen gradient between the lens and retina. Diabetic retinopathy is a frequent complication of diabetes, a disease that is reaching epidemic proportions world-wide. One of the strategies to treat advanced diabetic retinopathy is to remove the vitreous and replace it with silicone oil. Unfortunately, this treatment can have vision threatening complications such as cataract and glaucoma and does not treat the underlying mechanisms associated with diabetic retinopathy. We have developed a novel vitreous humor replacement to use instead of silicone oil and have performed a pilot study to evaluate its tolerability in the eye. Our preliminary data indicates that our new vitreous substitute does not introduce short term complications and can release antioxidants into the eye to help reduce oxidative stress, which is a contributor to diabetic retinopathy and cataract. This project will use the tissues we already have obtained and further analyze the samples for markers of inflammation and oxidative stress; we expect our novel vitreous substitute will reduce inflammatory and oxidative stress markers. Results from this project will allow future work to focus on clinical application of our vitreous substitute in diabetic patients. 

Fellowships (3)

OSU Ophthalmology

Fengze Wu

PI: Xiaoyi Raymond Gao

(year 1)

Automatic determination of vertical cup-to-disc ratio from fundus images using artificial intelligence

Glaucoma is a chronic, degenerative optic neuropathy and the leading cause of

blindness worldwide. It is a term used for a group of disorders that share a characteristic progressive excavation of the optic nerve head with associated and irrecoverable loss of the visual field. If untreated, glaucoma ultimately results in blindness. Individuals with glaucoma typically do not show symptoms for years and their case may become advanced before they notice an extensive visual field loss in one or both eyes. Early detection and treatment are crucial for preventing vision loss from glaucoma.

Glaucoma presents a significant disease burden. It affects 70-90 million people worldwide and is responsible for blindness in approximately 4.5 million people. Furthermore, about half of glaucoma cases are not aware that they have glaucoma even in developed countries. The US economic burden for glaucoma care is estimated at $2 .86 billion annually.

Vertical cup-to-disc ratio (VCDR), the ratio of (vertical diameter of cup)/(vertical diameter of disc) in the optic nerve head region, is an important structural parameter for glaucoma. People with glaucoma tend to have larger VCDR. As the disease progresses, the optic nerve fibers begin to die and the optic cup becomes larger in comparison to the disc. VCDR greater than 0. 7 is a typical criterion for glaucoma.

VCDR can be estimated by eye specialists during eye exams or from fund us images. However, this procedure is time-consuming and is subjective to personal experience. Automatic approaches deriving VCDR from fundus images not only reduce the manual burden, but also provide an objective and quantitative determination of VCDR.

This study aims to design and implement an automated system for determining VCDR from fundus images using a state-of-the-art artificial intelligence approach, addressing the critical need for an automated solution for glaucoma screening.

In this study, we proposed an automated deep learning approach for OD and OC segmentation and VCDR derivation from fundus images using Detectron2, a state-of-the-art object instance segmentation framework. We trained Mask R-CNN models for OD and OC segmentation and VCDR evaluation. We assessed the performance of our method on the Retinal Fundus Glaucoma Challenge (REFUGE) dataset in terms of the Dice index (DSC) for OD and OC, and the mean absolute error (MAE) for VCDR. Our method achieved highly accurate results with a DSC of 0.9622 for OD, a DSC of 0.8870 for OC, and an MAE of 0.0376 for VCDR on the hold-out testing images. This surpassed all REFUGE teams by improving OD and OC DSC over top performers by 0.2% and 0.4%, respectively, and reducing the VCDR MAE by 9%. Our method provided an accurate and automated solution for OD and OC segmentation and VCDR estimation.

Univ. of Cincinnati

Jhuwala Venkatakrishnan

(PI Winston Kao)

(year 5)

 

Cystinosis is a genetic disorder of the eye which is caused by the mutation in the cystinosin gene (CTNS). Cystinosin gene encodes cystine/proton co-transporter that is responsible for exporting the amino acid, cystine, from lysosomes of  cells. Mutation of this gene leads to the accumulation of cystine in the lysosomes of the cells and forms cystine crystals. This leads to impaired cell function and organ damage. The prominent organs affected are eyes and kidneys. Cystinosin is the most common cause of inherited Fanconi syndrome in young children. Owing to the rarity of the disease, treatment and diagnosis of the disease is frequently delayed. This considerably impacts the overall prognosis of the patients. Current effective treatment method is the application of cysteamine. But cysteamine is toxic to multiple tissues and organs. Development of animal model of cystinosis to study the disease in detail is critical for development of effective treatment regimen for cystinosis. Moreover, advancements in gene therapy methods suggest a potential role in treating genetic disorders. Specifically, use of Adenoviral vectors in introducing functional transgenes into the cells is a promising approach. In our project, we aim to develop animal model of cystinosis and determine the effect of adenoviral vectors carrying the functional cystinosin transgene in reducing the cystine crystals of the eye.

OSU Optometry

Erica R. Shelton

(PI: Dean A VanNasdale)

Vision-Related Quality of Life in the School-Aged Population of Appalachian Ohio

Public Heath’s first step in addressing a problem at a population level is a stable and effective surveillance mechanism to monitor data for trends to identify populations in need of interventions.[24] As noted in the problem statement, I spent most of my early doctoral program working toward harmonizing data related to pediatric vision health. The results demonstrated a need for interventions in the school-aged population to improve compliance after a failed vision screening. This work will help provide additional evidence that there are multiple interacting factors that result in barriers to vision care services and that appropriate vision care for those in greatest need has broader impacts beyond scholastic performance (attendance, self-esteem, etc.).  The development and validation of a data-driven pediatric vision health survey for use in other pediatric vision programs is an imperative step to addressing the pediatric vision health dilemma. This will allow for other states engaging in school-based vision clinics to be compared across a similar metric and for the inclusion of a metric that considers the functionality of the entire child.

Grants related to AMD (3)

Institution       

 

Wright State University

Dr. Organesiak has retired.

OSU Optometry

Deyue Yu

Development of Remote Assessment methods to Assess Visual Function in AMD Patients

Age related macular degeneration (AMD) is the leading cause of vision loss among adults 50 years and older in the United States. There are about 11 million Americans who suffer from AMD and that number is projected to almost double in the next 25 years. A comprehensive assessment of the patient’s functional vision is crucial in providing effective low vision care to these patients. However, such assessment can only be carried out in the clinic or laboratory, often requires hours of strenuous effort from the patient, and heavily relies on customized devices. During the COVID-19 pandemic, telehealth became a convenient way of delivering vision care. As tele-visits continue to grow in popularity, the demand to assess performance remotely without using customized device is increasing. There is a clear need for assessment methods that can provide reliable performance measures outside the clinic with simple setups and easy tasks. Here, we propose to develop solutions to address the need. We will develop novel subjective evaluation procedures utilizing guided subjective self-report to measure reading-related visual performance. If successful, the proposed solutions would allow us to assess visual functions of AMD patients remotely and allow patients to self-monitor changes in their visual status and intervention outcome in a simple and reliable way.  

OSU Ophthalmology

PI: Nagarai Kerur, PhD

AMD: Unraveling Inflammatory Mechanisms in Aging Eye

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMO} characterized by central vision loss due to retinal-pigmented epithelium (RPE) cell death. Aging is the most important risk factor for AMO. Emerging data suggests that pathogenesis of GA is linked to over-activation of a tissue-damaging immune pathway. However, the connection between aging and the mechanism by which aging influences over-activation of tissue-damaging immune responses in AMO is currently not known. Here, we hypothesize that, aging-associated DNA damage in eyes with AMO is responsible for the over-activation of the tissue-damaging immune pathway.

Cincinnati

PI: Yoonjee Park/ Chia-Yang Liu

 

Long-term Antibody Implant for Age-Related Macular Degeneration Treatment In Vivo

Specific Aims

Age-related macular degeneration (AMD) is a degenerative retinal disease that causes progressive loss of central vision. AMD is the leading cause of irreversible vision loss and legal blindness in individuals over the age of 50. As many as 11 million Americans have some form of macular degeneration, including both early and later stages of the wet and dry forms. This number is expected to double by 2050.

Current treatment methods are direct intraocular injections of drug (e.g., Avastin or Lucentis) every 4~6 weeks. However, these multiple frequent injections are not only invasive and inconvenient for patients but also increase the risk of complications, such as retinal detachment, traumatic cataract, etc, which often require surgical interventions that may have a high risk of the patients losing their eyesight, while also leading to high treatment costs. Therefore, it is necessary to develop an effective drug delivery method for a long term to maintain effective drug dose for therapeutic efficacy while avoiding frequent injections.

This research focuses on the development and optimization of an dose-controllable and personalized long-term drug delivery device. A 10 mm-sized tube with 0.8 mm in diameter made of biodegradable polymer capsule will be used to encapsulate the drug (Avastin) and the dexamethasone, anti-inflammation drug, will be released from the capsule. The capsule can be intravitreally injectable into the eye, and releases drug in a sustainable manner for 6 months and longer, which can eliminate the monthly invasive injections. We will examine the drug delivery efficacy with a rabbit disease model.

Successful completion of the proposed research will clinically translate into effective AMD treatment characterized by a finely controlled drug release and enhanced drug delivery with a reduced injection frequency and treatment cost. The innovative ocular endeavors will improve visual outcomes and quality of life for those who are blind or visually impaired.

Lois Hagelberger-Huebner Young Investigator Applications (1)

Applicant       

PI: Ann M. Morrison

OSU Optometry

Emmetropization Via Accommodation

Infants do not usually wear glasses because they usually do not need them to see clearly. Most infants are born with a moderate amount of farsightedness. This is not a problem because there is a process called 'emmetropization' that reduces the amount of farsightedness, placing most infants' eyes right where they need to be in order for them to see clearly by their first birthday. However, up to 10% of infants do not emmetropize properly and end up with eyes that are shorter than normal in length, resulting in a very farsighted prescription (refractive error). These are usually the babies with the highest amounts of farsightedness at birth. Infants are not typically examined by eye care professionals in the United States, meaning that severe levels of farsightedness are often left uncorrected. Farsighted infants must use extra focusing effort to see clearly, which may make their eyes cross and perhaps cause a "lazy eye". Highly farsighted infants are 122 times more likely to develop an eye turn compared to infants with no clinically significant prescription. If infants avoid the extra focusing effort and their vision stays blurred into childhood, they are 5 times more likely to develop two lazy eyes. Not only do highly farsighted children have increased risk for visual problems, they can suffer from poor literacy and academic performance. A recent study found that preschool-aged children who had moderate amounts of farsightedness scored worse on early literacy testing compared to their peers who did not have as much farsightedness or no refractive error. Deficits in early literacy can have lasting implications for children. The Annie E. Casey Foundation Research Report from 2011 found that 1 in 6 children who are not reading proficiently in 3rd grade to not graduate from high school on time, a rate 4 times greater than that for proficient readers. The report also found that 23% of low, below-basic readers drop out or fail to finish high school on time. Clearly, high amounts of farsightedness at birth and a failure to emmetropize can have serious consequences for years to come. 

The purpose of this project is to determine if emmetropization can be enhanced in very farsighted babies and reduce the high farsightedness that puts them at risk for more vision problems. Participants were randomized to receive either partial correction or no correction. The comparison group (control group) will be farsighted babies who receive the current standard care, namely no correction but monthly monitoring. If randomized to the correction group, the infant will be given glasses with a partial correction, an amount that is less than their full degree of farsightedness but enough to put them in the zone of effective emmetropization. This "boost" is meant to enable very farsighted babies to use their eyes in a normal way and emmetropize as normal infants. Parents of subjects in the intervention group will also be instructed to provide 20 minutes per day of visual engagement with their infant in order to encourage accurate accommodation. This partial correction is given at 3 months of age for a period of up to 15 months. Research has shown that most emmetropization takes place within this narrow window of time, from 3 to 9 months of age, suggesting that treatment periods past the age of 9 months are unlikely to be effective.

If emmetropization can be enhanced in very farsighted babies, the risk of developing crossed eyes, lazy eyes, or deficits in early literacy and learning will be reduced. The lifelong need for spectacles, contact lenses, or refractive surgery for high amounts of farsightedness would also be reduced, if not eliminated. Positive results might also make infant eye examinations more common and place a new therapeutic option in clinicians' hands. A few months of glasses wear may prevent a lifetime of vision and learning problems.

 

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