2007 — 2011 |
Hackam, Abigail Shoshana |
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. |
Wnt Signaling and Neuroprotection in the Retina @ University of Miami School of Medicine
[unreadable] DESCRIPTION (provided by applicant): Photoreceptor death underlies many types of retinal degeneration, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Our long-term goal is to understand mechanisms of photoreceptor survival. During retinal injury, Muller glia cells play a protective role by secreting pro-survival growth factors to protect remaining photoreceptors in a toxic environment. The signaling pathways that lead to growth factor induction are largely unknown. Therefore, elucidating the molecular mechanisms that regulate growth factor induction will be important for understanding the potential therapeutic properties of these important molecules and for identifying novel, more effective, treatments. The Wnt pathway is an essential signaling cascade that mediates retinal development and retinal stem cell proliferation and is a critical regulator of cell survival in degenerative conditions of the brain, such as Alzheimers disease. Several lines of evidence suggest that Wnt signaling is protective in the retina and that it may induce growth factors from Muller glia or act directly on photoreceptors. Our hypothesis is that Wnt signaling plays a pro-survival role during retinal degeneration. In this study we will delineate the role of Wnt signaling in the Muller glia- growth factor injury response using primary Muller glia cultures (Aim 1). To identify the role of Wnt signaling during retinal degeneration we will use viral vectors to over-express Wnt activators and inhibitors in primary retinal cultures and in vivo (Aims 2 and 3). Together, these experiments will advance our understanding of pathways regulating photoreceptor survival and will identify a new cellular signaling mechanism linking photoreceptors and Muller glia. Furthermore, the results from this study will demonstrate whether modifying the Wnt pathway can be used as a therapeutic strategy for retinal degenerations. [unreadable] [unreadable] [unreadable]
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0.978 |
2017 — 2020 |
Hackam, Abigail 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. |
Mechanisms of Optic Nerve Regeneration @ University of Miami School of Medicine
Degeneration of retinal ganglion cells (RGCs) and atrophy of their axons in the optic nerve are hallmarks of many ocular diseases and result in permanent vision loss. There is a critical need for new therapeutic strategies that induce robust axonal regeneration7KHFDQRQLFDO:QW?-catenin (?Wnt?) signaling pathway is one of several different Wnt pathways that regulate axon growth in the developing CNS. Although canonical Wnt ligands are known to be important for developmental axonal growth and neuronal viability throughout the CNS, their role in RGC axonal growth in adults after optic nerve injury is unknown. We recently demonstrated the novel finding that a single intravitreal injection of recombinant canonical Wnt3a ligand led to significant axon regeneration after murine optic nerve crush injury. In this project, we will ask whether repurposing the developmental axonal growth properties of canonical Wnt ligands can be used as a potential therapeutic strategy for axonal regeneration after optic nerve injury. Additionally, we will investigate how non-neuronal cells in the retina contribute to optic nerve regeneration and whether they modulate the activity of pro-regenerative factors. We demonstrated using a Wnt reporter transgenic mouse that Wnt3a-induced optic nerve regeneration was associated with upregulated Wnt signaling in the Muller glia and RGC, suggesting that Wnt promotes axonal regeneration by acting intrinsically within RGCs as well as extrinsically in non-RGCs such as Muller glia. Our central hypothesis is that activation of Wnt3a signaling within the retina leads to axonal regeneration, and that Wnt3a-induced axonal growth requires the involvement of Wnt signaling within both RGC and Muller glia. In Aim 1, we will build upon our promising preliminary data and will test the extent and duration of Wnt3a-induced axon regeneration after optic nerve crush in transgenic Wnt reporter mice at the functional and morphological levels, will determine the amount and localization of activated Wnt signaling and will identify underlying molecular mechanisms. In Aim 2, we will identify cellular mechanisms of axonal growth by determining the contribution of RGCs and Muller glia to Wnt- induced regeneration using cell-specific Wnt inhibitor and activator constructs. The collaborative team of the PI, an expert on Wnt and Muller glia, Dr. Kevin Park, an expert on optic nerve regeneration, and Drs. Ivanov and Porciatti, experts on RGCs, is uniquely suited to perform this study. This study will have a high impact on the field by defining a novel pro-regenerative activity for Wnt3a on the optic nerve, which will enhance the overall understanding of regeneration pathways and will identify novel targets for RGC regrowth. These findings could be applied to developing new therapies for regenerating damaged optic nerves, including traumatic injury, optic neuropathies, retinal ischemia and late stage glaucoma.
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0.978 |
2019 |
Hackam, Abigail S |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Shared Equipment Module @ University of Miami School of Medicine
The Shared Equipment Project Summary information is included in other sections of the application.
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0.978 |
2021 |
Hackam, Abigail S |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Experimental Models Core @ University of Miami School of Medicine
EXPERIMENTAL MODELS MODULE Summary The purpose of the Experimental Models (EM) Module is to provide expert service and assistance for a large variety of in vivo testing and procedures, help facilitate all experiments using animal models performed by MVRC investigators, and to enable them to develop new interdisciplinary projects. Specific Aims are: 1) To provide expert services and assistance, through the use of specialized equipment and experienced personnel, for a large variety of surgical and non-surgical procedures for experimental vision research in mice, rats, rabbits, cats, dogs, pigs and non-human primates, 2) To provide training to all investigators on established procedures and assist investigators to develop new procedures, including new surgical methods, drug delivery and generation of mito-mice, 3) To serve as a resource center for fostering new collaborations among MVRC scientists and clinicians, and for sharing animal models, biological tissues and genotyping protocols, 4) To consult and assist with IACUC protocols, including protocol writing and compliance. Experienced personnel and specialized equipment are available in this module for vision researchers. This module is essential for numerous basic science and translational research studies at BPEI, as indicated by its extensive use by most of our NEI-funded investigators. In the last funding period, the EM module was used to generate data that was reported in numerous publications and included in new grant awards. Furthermore, this module has been essential in developing novel electrophysiological and behavioral assessment of vision in rodents, for creating inducible animal models of glaucoma, diabetes, and macular degeneration, testing novel gene therapies, and investigating environmental influences on animal models of retinal disease through the use of the rodent smoking machine and specific nutrition modifications. This module will continue to provide an essential resource for cutting-edge research of MVRC investigators.
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0.978 |