RAB5 AND PI-3-KINASE AND GENTAMICIN TOXICITY

Project: Research project

Description

DESCRIPTION: Aminoglycosides are a widely used class of antibiotics. They are commonly prescribed for the treatment and prevention of gram-negative bacterial infection. Although very effective, they can also induce well known toxic side effects. These effects are primarily expressed as damage to the kidney and inner ear, nephro- and ototoxicity, respectively. If administration is terminated the kidney rapidly recovers, however, damage arising in the inner ear can be irreversible. Due to the wide spread and common use of these antibiotics, this toxicity represents a significant clinical and financial burden on the health care system. Inhibition of many cellular processes has been described, but characterization of a specific mechanism has remained elusive. The long term goal of this application is to better characterize the mechanism of aminoglycoside-induced nephrotoxicity. Recent evidence suggests that components involved in inducing endocytosis and fusion of endocytic vesicles, specifically the proteins Rab5 and phosphatidylinositol-3-kinase (PI-3-K), may play a role in aminoglycoside toxicity. Disruption of these processes by inhibition of these 2 proteins' activity could lead to the toxicity that is seen with prolonged aminoglycoside treatment. These proposed studies are designed to look at levels (Rab5), subcellular localization (Rab5), and the activity (Rab5 and PI-3-K) of these proteins in a well characterized rat model of aminoglycoside-induced nephrotoxicity. The rat model of aminoglycoside-induced nephrotoxicity is very similar to the human situation and has been very successfully used as an in vivo model of human toxicity. Rats will be injected with gentimicin (the most commonly used aminoglycoside) for short- (3 days) and long term (18 days) periods. The day following the last injection, effects of gentamicin treatment on the parameters mentioned above will be characterized using morphological and biochemical techniques. By performing these studies, it is hoped that formulation of specific therapies to delay and/or inhibit this toxicity will become possible.
StatusFinished
Effective start/end date9/18/988/31/04

Funding

  • National Institutes of Health: $155,108.00

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Aminoglycosides
Gentamicins
Phosphatidylinositol 3-Kinases
Phosphatidylinositol 3-Kinase
Inner Ear
rab5 GTP-Binding Proteins
Gram-Negative Bacterial Infections
Anti-Bacterial Agents
Kidney
Transport Vesicles
Poisons
Endocytosis
Proteins
Therapeutics
Delivery of Health Care
Injections

ASJC

  • Medicine(all)