The main topics of exploration in the Hackam laboratory are the analyses of genes and pathways involved in photoreceptor degeneration, the molecular pathogenesis of ocular tumors, and the genetic basis of human retinal disease.
1. Identification of photoreceptor protective proteins: the role of the Wnt signaling pathway in retinal degeneration.
The retina is a thin multi-layer tissue at the back of the eye that is essential for vision. Degenerative diseases of the retina, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), lead to visual difficulties and eventual loss of sight. These diseases are a result of damage and death of photoreceptors, the light-sensing cells in the retina. The treatment of retinal degeneration diseases requires a better understanding of molecules involved in regulating photoreceptor survival. A major focus of our research is identifying and characterizing photoreceptor protective factors.
Our recent analyses indicate that the Wnt signaling pathway, a critical intercellular communication pathway, protects photoreceptors from degeneration. The current focus is on understanding the mechanism of action of Wnt signaling, the cell types involved, and whether we can use Wnt ligands as a novel therapeutic for retinal disease.
2. The role of inflammation in retinal degeneration.
Our recent work has demonstrated that neuroprotective Wnt signaling is suppressed by pro-inflammatory pathways. Current experiments focus on understanding how Wnt is regulated during inflammation, which will provide insight into cross-talk between inflammation and neuroprotection during retinal degeneration.
3. Mechanisms of tumorigenesis and cancer stem cell proliferation in ocular cancer.
We have identified the Wnt pathway as a novel suppressor in retinoblastoma (RB) tumor cells, which is the most common primary intraocular eye cancer in children. Furthermore, Wnt signaling regulates the number of cancer stem cells in retinoblastoma. Our current experiments are to understand the mechanisms of action of Wnt signaling, and whether manipulating the Wnt signaling pathway has potential as a novel therapeutic strategy for retinoblastoma. Because most cancer cells contain inactivating mutations in the Rb1 gene, we expect that our data on the intersection of Wnt and Rb1 pathways will be applicable to many other types of tumors.
4. Identification of genetic pathways in retinal degeneration.
We have used custom retinal microarrays to compare gene expression changes in retinal degenerations in various mutant rat and mouse disease models. A main interest is to determine at what point degenerations that occur at different rates, or are induced by different genetic mutations, converge along shared pathways towards apoptosis. These experiments will provide insight into mechanisms of cell death in the retina and could indicate whether general therapeutic intervention, rather than mutation-specific methodologies, would be effective.
5. Identification of mutated genes in human retinal disease.
Microarray analysis of normal and degenerated retina and comprehensive bioinformatics analyses have identified a large number of photoreceptor-expressed genes that are localized within critical chromosomal regions for inherited retinal disease. These genes can be considered good candidates for involvement in retinal disease, and studies are being planned to collect blood samples from affected individuals for mutation screens of these genes.
6. Drug discovery.
We have developed a Muller glia-photoreceptor culture system that enables us to test novel compounds that regulate photoreceptor survival.