The ability to read this page without magnification depends upon the integrity of the macula, a small region of the retina including the fovea. Macular degeneration is the leading cause of blindness in developed countries. Age-related macular degeneration (AMD) is a progressive degeneration of the macula that affects approximately 20% of individuals over the age of 65, but its causes remain unknown. The hypothesis driving this proposal is that CI currents play a role in phagocytosis of shed photoreceptor discs by the retinal pigment epithelium (RPE). Defects in this process can lead to macular degeneration as the result of accumulation of retinoids and lipofuscin pigment in the subretinal space. We propose that CI channels are important in normal phagocytosis because they are involved in the regulation of cell volume during ingestion of large quantities of outer segments. A variety of well-known CI channels including CFTR, CIC-2, CIC-3, and CIC-5 are expressed in RPE cells and recently it has been suggested that bestrophin, an RPE protein that causes Best macular dystrophy, is the founding member of a new family of CI channels. The goal of this project is to characterize the CI currents, especially bestrophin-mediated currents, that are expressed in RPE cells and to understand their function. There are three specific aims. (1) To determine the properties of bestrophin CI channels. We will test the hypothesis that bestrophins are subunits of a chloride channel by patch clamp analysis of heterologously expressed bestrophins. (2) To characterize chloride channels in RPE cells.
This aim tests the hypothesis that several types of CI channels are functionally specialized for specific RPE functions. The strategy is to use whole-cell and patch clamp recording to characterize CI channels in RPE cells and to compare them to the properties of known CI channels, including bestrophin. (3) To determine the role of CI channels in photoreceptor disc phagocytosis.
This aim will test the hypothesis that CI channels are important in phagocytosis of rod outer segments by RPE cells. This hypothesis will be tested by determining the effects of pharmacological inhibitors and antisense knockdown of CI currents on the phagocytosis of rod outer segments by RPE.
| Omotade, Omotola F; Rui, Yanfang; Lei, Wenliang et al. (2018) Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation. J Neurosci 38:10271-10285 |
| De Jesús-Pérez, José J; Cruz-Rangel, Silvia; Espino-Saldaña, Ángeles E et al. (2018) Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1). Biochim Biophys Acta Mol Cell Biol Lipids 1863:299-312 |
| Whitlock, Jarred M; Hartzell, H Criss (2017) Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles. Annu Rev Physiol 79:119-143 |
| Jiang, Tao; Yu, Kuai; Hartzell, H Criss et al. (2017) Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase. Elife 6: |
| Cruz-Rangel, Silvia; De Jesús-Pérez, José J; Aréchiga-Figueroa, Iván A et al. (2017) Extracellular protons enable activation of the calcium-dependent chloride channel TMEM16A. J Physiol 595:1515-1531 |
| Fisher, Skylar Id; Hartzell, H Criss (2017) Poring over furrows. Elife 6: |
| Whitlock, Jarred M; Hartzell, H Criss (2016) A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid. Pflugers Arch 468:455-73 |
| Hartzell, H Criss; Whitlock, Jarred M (2016) TMEM16 chloride channels are two-faced. J Gen Physiol 148:367-373 |
| Griffin, Danielle A; Johnson, Ryan W; Whitlock, Jarred M et al. (2016) Defective membrane fusion and repair in Anoctamin5-deficient muscular dystrophy. Hum Mol Genet 25:1900-1911 |
| Contreras-Vite, Juan A; Cruz-Rangel, Silvia; De Jesús-Pérez, José J et al. (2016) Revealing the activation pathway for TMEM16A chloride channels from macroscopic currents and kinetic models. Pflugers Arch 468:1241-57 |
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