The broad goal of the proposed research is to understand the molecular arrangements of aquaporins in a living cell membrane. We wish to observe in real time the mechanisms by which aquaporins interact during water transport, and in conjuction with ion transport. The studies outlined here will directly address the molecular motions of aquaporins in the living membrane by tracking attached fluorescent particles called quantum dots. These studies will first focus on aquaporin arrangements alone. The physical motions and spatial arrangements of aquaporins during water transport will facilitate a better understanding of its role in response to brain injury and tumor cell migration. Co-localization experiments will determine in detail the interaction between aquaporins and potassium channels that may be crucial to the maintenance of ion gradients that preserve normal brain function and prevent epileptic seizures. The primary water channel in the brain is aquaporin-4. Since its discovery, its known role in the health of the central nervous system has been significantly expanded. When an injury occurs in the brain, swelling of soft tissues can cause severe damage due to their enclosure in the rigid cranium. Therefore, a path for rapid water transport must be readily available. Aquaporin-4 levels are upregulated in response to tumors, but this upregulation may actually serve to facilitate the spread of the aggressive types of cancer, which makes it an attractive target for cancer drug development. However, while the inhibition of aquaporin-4 may potentially slow the spreading of tumors, this may have severe consequences in other aspects of health. For example, the removal of aquaporin-4 leads to an increase the in the severity of edema caused by various types of brain injury. Recent evidence indicates a primary role of aquaporin-4 in the maintenance of potassium levels in the brain, possibly through molecular coupling of water and potassium channels. The removal of aquaporin-4 leads to a significant delay in the reuptake of potassium by cells in the neural cortex. Any imbalance in potassium levels in the brain can lead to the onset epileptic seizures. The range and severity of diseases that potentially involve aquaporin-4 is substantial. Epilepsy affects over 2 million Americans and results in a severly diminished quality of life. Malignant tumors in the brain are less common, but are almost universally fatal. An understanding of the molecular mechanishms behind these various roles of aquaporin-4 in the health of the central nervous system are a necessary step before considering the targeting of aquaporin-4 for treatment of disease. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F03B-L (20))
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Flicker, Paula F
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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