Iris S. Kassem, MD, PhD - US grants

DESCRIPTION (provided by applicant): Hemifacial spasm generally begins as involuntary muscle spasms in the eyelids and then progresses to the entire distribution of the facial nerve. This disease is thought to be due to a compression of the facial nerve at its root entry zone by one of several arteries in the region. The underlying neural mechanisms of the hemifacial spasm are still controversial. Arterial compression of the nerve can modify the facial nerve, facial motoneurons, and the trigeminal nucleus. This proposal investigates the role of each of these modifications in producing the symptoms of hemifacial spasm. Hemifacial spasm patients will used to identify changes in the trigeminal system. An animal model isolating the different mechanisms will be created to characterize the causes of symptom development resulting from motoneuron and trigeminal modifications.

DESCRIPTION (provided by applicant): This application is requested to further the career development of an academic pediatric ophthalmologist with a scientific interest in elucidating the response to intraocular surgery and discovery of novel therapies to prevent or treat postoperative complications in children and improve visual outcomes. The short-term goal is to develop the candidate's career as a clinician-scientist by expanding her understanding of ocular immunology and pathology and improve her research design, techniques and analysis skills. This will be achieved with mentorship, practical training, coursework, and involvement in a network of investigators. The environment at the University of Illinois is an ideal institution fo the candidate to transition to independence because of the available facilities, faculty, staff, an financial support. The priority of the Medical School and Department of Ophthalmology and Visual Sciences at the University of Illinois are to nurture early career clinician-scientists into independent investigators. They have demonstrated this commitment in the form of material, financial, technical, and administrative support for the candidate to achieve the goals of this proposal. There is a significant clinical need for the prevention and treatment of postoperative complications from exaggerated inflammation and fibrosis in children because of the risk of irreversible decreased vision from amblyopia. The objective of this proposal is to establish age-related changes in aqueous humor inflammatory mediators and determine the effect of pharmacologic intervention on inflammation and fibrosis after intraocular surgery. This will be accomplished with three specific aims: Specific Aim 1. Establish differences in aqueous humor inflammatory mediators before and after intraocular surgery in children and adults. Intraocular fluid samples from subjects who are surgically naïve and with a history of surgery will be analyzed with a Multiplex Bead-Based Immunoassay to simultaneously determine the levels of multiple inflammatory mediators. This will determine which proteins may be involved in the age-related response differences to intraocular surgery. Specific Aim 2. Determine changes in inflammation and fibrosis before and after intraocular surgery with aging in a rabbit model. Lensectomy of juvenile, adolescent, and adult rabbits without postoperative treatment will be used as a model of age-related differences in response to intraocular surgery. Analysis of aqueous humor inflammatory protein levels and comprehensive evaluation of clarity of the visual axis, inflammation and fibrosis, intraocular pressure, and corneal thickness will be used to systematically evaluate the response to lensectomy as rabbit's age. This will determine how aging affects inflammation and fibrosis in a rabbit model of lensectomy. Specific Aim 3. Determine the effect of intraocular pharmacologic intervention on inflammation and fibrosis in a juvenile rabbit model of lensectomy. Inflammatory mediator levels will be analyzed, along with standardized postoperative evaluation of clarity of the visual axis, inflammation and fibrosis, intraocular pressure, and corneal thickness. This will identify the most effective pharmacologic intervention for the prevention and treatment of postoperative inflammation and fibrosis following juvenile rabbit lensectomy. The findings from this proposal will serve as the scientific and technical foundation for future studies characterizing the response to intraocular surgery. These studies will identify novel age-related responses in eyes that may cause adverse outcomes after intraocular surgery in children. A clear understanding of the processes that result in complications from surgery will aid in the discovery of effective therapies. With effectie preventative and therapeutic interventions, we can have a lifelong impact by improving visual outcomes in children. The training, mentoring, and career development plan in this proposal will transition the candidate to an independent investigator making long-lasting contributions to the visual science community and vision care.

PROJECT SUMMARY Lysosomal storage diseases are systemic metabolic disorders caused by pathologic accumulation of byproducts in various cells and organs, including the eye. Fabry disease is the most common lysosomal storage disease and results from a mutation of the X-linked GLA gene causing a deficiency of the enzyme ?-galactosidase A (?-Gal A). Glycosphingolipids progressively accumulate, resulting in a shorter and poorer quality of life from renal failure, cardiac dysfunction, cerebrovascular disease, gastrointestinal symptoms, and chronic pain. Patients also have pathognomonic cornea verticillata that is usually present at the time of diagnosis. Other symptoms include cataract, conjunctival and retinal tortuosity, and aneurysmal dilation. Importantly, a direct correlation exists between the prevalence of certain ocular findings and disease severity in Fabry disease with cornea verticillata often leading to the initial diagnosis. The timing of the ocular findings relative to other organ system disease is not well described and difficult to study in humans because of heterogeneity in the patient population. Mouse models have been used in the development of enzyme replacement therapy (ERT), but are limited by the fact that they do not recapitulate ocular phenotypes. Using a Dark Agouti ?-Gal A knockout animal model with the corneal, lenticular, and retinal vascular changes seen in patients, we seek to evaluate both knockout rats and humans for an ocular pain and retinal phenotypes not previously evaluated in a in a cohort for this rare disease. Our unique approach integrates the complementary strengths of an animal model, giving the opportunity to study a large controlled population, while human studies determine the clinical significance of pathology. We propose to do this with the following specific aims: 1) evaluate the extent and time course of ocular pathology in a ?-Gal A KO rat model of Fabry disease and the effect of early versus later ERT and 2) evaluate human subjects with Fabry Disease for ocular pain and subclinical ocular changes that precede clinically significant disease observed in ?-Gal A KO rats. This work is expected to have a significant impact on our understanding lysosomal storage diseases by using an animal model that recapitulates eye symptoms to elucidate the time course of ocular pathology of Fabry disease in relation to systemic symptoms. These findings will aid in the determination of optimal timing of ERT initiation and the efficacy of new therapies, while providing mechanistic insight into the ocular pathology of other lysosomal or metabolic diseases.

ABSTRACT The Medical College of Wisconsin prioritizes research as one of its missions and includes in its strategic plan ?accelerating discovery with cutting-edge, evidence-based research.? With this support we request funds for the shared instrumentation of a Leica Microsystems Proveo 8 ophthalmic surgical microscope with intrasurgical EnFocus optical coherence tomography. The equipment would be used by eleven faculty from four departments from two institutions. We describe four major thematic programs and four additional minor projects that will be supported by eleven users, including five major and six minor users. Uses for the equipment includes ophthalmic, vascular, and oncologic, along with teaching applications. This instrument is requested to replace two outdated operating microscopes. The requested equipment would provide video documentation to increase rigor and transparency of research. It would also improve procedures to reduce and refine the use of animals in research projects. A compact footprint will decrease space requirements. This state-of-the-art instrument will help advance NIH-funded research and help future research applications in southeast Wisconsin.