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NIDCR Team Creates Mouse Model of Disease

A team led by scientists at NIDCR has created a mouse model with tooth defects similar to those of people with dentinogenesis imperfecta III, a hereditary disorder in which the teeth can wear down to the innermost pulp. Dr. Ashok Kulkarni and his colleagues created the animal model by "knocking out" the dentin sialophosphoprotein (DSPP) gene, thought to be responsible for coordinating the mineralization, or maturation, of a tooth's dentin. The researchers recently reported their findings in the Journal of Biological Chemistry.

The DSPP knockout animals are the most recent addition to a long list of mouse models created by the NIDCR functional genomics unit and gene targeting facility headed by Kulkarni. "The goal of our lab is to characterize the precise functions of candidate genes involved in development and disease," he said. "Many genes have been identified, but the exact in vivo functions of only a few have been described."

Members of the NIDCR functional genomics unit and gene targeting facility include Dr. Ashok Kulkarni (seated) and (back row, from l) Dr. Taduru Sreenath, Glenn Longenecker, Bradford Hall and Dr. Tamizchelvi Thyagarajan.

The group, and its many collaborators, is credited with developing mouse models for hereditary dental defects, including the first animal model for a tooth-specific gene called amelogenin. Their other models include those for autoimmune and neuro-degenerative disorders and Fabry disease. Created in collaboration with Dr. Roscoe Brady's group at NINDS, the Fabry model has proved valuable to researchers in developing new treatment strategies for this often-fatal metabolic disorder.

"Active collaboration across disciplines, both inside and outside NIH, was the key to all these projects," said Kulkarni. "And everyone benefits. Because when you study disease processes at the molecular level, what you learn can be applied to a variety of diseases and disorders that affect many organs and tissues."

IC Study Finds Limited Benefit in Two Drugs

An 18-month pilot study of two commonly available treatments has shown no significant benefit in patients with interstitial cystitis (IC). The results are reported in the September issue of the Journal of Urology.

The first in a series of treatment studies planned by the IC clinical trials group tested the effectiveness of pentosan polysulfate sodium (Elmiron) and hydroxyzine hydrochloride (Atarax) in 121 patients with IC. Most volunteers reported experiencing moderate pain, discomfort and urinary frequency for at least a year before entering the study.

IC is a chronic, debilitating condition that affects about a million people, most of them women. Patients suffer pelvic, bladder or perineal pain and the urge to urinate as often as 18 times a day. Available treatments are limited and not effective for everyone. The National Institute of Diabetes and Digestive and Kidney Diseases initiated the clinical trials group in 1998 to identify useful therapies for this devitalizing and difficult disease with no known cause and no cure.

Elmiron and Atarax were chosen for early testing because patients prefer oral drugs and each drug has different mechanisms of action. Elmiron is the only oral drug approved by the FDA for IC. Doctors do not know exactly how it works, but one theory is that it may repair defects in the lining of the bladder. In some patients, mast cells are present in the tissue of the bladder wall, possibly a sign of an allergic or autoimmune reaction. Atarax, an antihistamine previously untested in a randomized, placebo-controlled trial for IC, reduces mast cell activity. Mast cell activity can cause bladder inflammation and pain and may play a part in IC.


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