Phosphatases as a Novel Therapeutic Targets for Adenotonsillar Hypertrophy of Pediatric Sleep Apnea
University of Chicago
posted on 02/04/2010
Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality. Dr. David Gozal and his group at the University of Chicago have identified a candidate list of tonsil-proliferative genes in OSA. In vitro studies using a mixed tonsil cell culture system targeting one of these candidates, phosphoserine phosphatase (PSPH), revealed that it was more abundantly expressed in tonsils of OSA children, and that pharmacological inhibition of PSPH led to marked reductions in T and B lymphocyte cell proliferation and increased apoptosis. Furthermore, functional studies confirm a novel role for protein phosphatases in AT hypertrophy, and may provide a promising strategy for discovery of novel, non-surgical therapeutic targets in pediatric OSA.
Suggested Uses
Non-surgical treatment of pediatric obstructive sleep apnea which is a prevalent disorder affecting up to 2-3% of children that
imposes substantial neurocognitive, behavioral, metabolic, and cardiovascular morbidities.
Advantages
The usual treatment for pediatric sleep apnea, i.e., tonsillectomy and adenoidectomy, is costly, and fraught with measurable adverse consequences ranging from mild events such as pain to serious complications such as hemorrhage, infections, acute respiratory insufficiency, and potentially death. Therefore, effective non-surgical strategies for the treatment of pediatric sleep apnea are imperatively needed and can dramatically impact clinical practice.
Detailed Description
Pediatric sleep apnea is a common disorder primarily caused by enlarged tonsils and adenoids impinging upon the patency of the upper airway during sleep. Mechanisms leading to the proliferation and enlargement of the tonsils and adenoids in children who subsequently develop obstructive sleep apnea remain unknown.
Dr. David Gozal and colleagues at the University of Chicago have performed genome-wide transcriptional profiling of tonsillar tissues obtained from children with and without OSA and outlined a computational framework to identify novel candidate targets regulating adenotonsillar hypertrophy. They have validated their unbiased approach by performing follow-up in vitro proliferation assays to demonstrate that selective targeting of two up-regulated candidate genes, PSPH and DUSP1, profoundly reverses the proliferative state of adenotonsillar tissue in OSA. Thus, phosphatases play a critical role in pediatric tonsillar hypertrophy, and mediate the mechanisms leading to this proliferative state selectively in children with OSA.
Phosphoserine phosphatase belongs to a subfamily of phosphotransferases and catalyzes the rate-limiting step in serine biosynthesis by converting L-phosphoserine to L-serine. Dr. Gozal group have used several strategies to target PSPH expression and activity in adenotonsillar primary cell cultures, including pharmacological and siRNA inhibition, resulting in significant anti-proliferative effects specifically in cell cultures derived from children with OSA. Furthermore, they have shown that inhibition of PSPH appears to promote programmed cell death in tonsillar cell cultures. Together, these observations suggest
that PSPH is a logical therapeutic target in reversing the adenotonsillar enlargement of pediatric OSA.
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