The "metabolic syndrome", a constellation of metabolic and cardiovascular anomalies that heavily impact the morbidity and mortality of obese individuals, frequently complicates successful treatment for obesity. Obesity- associated insulin resistance plays a central role in the pathogenesis of the metabolic syndrome, and insulin signaling is an important focus in obesity research. Several protein tyrosine phosphatases recently emerged as critical negative regulators of insulin signaling and quickly became popular targets of drug development efforts for obesity and type 2 diabetes. This grant focuses on a tyrosine phosphatase called the low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the Acp1 gene. The LMPTP is highly expressed in insulin- target tissues and several data suggest it is a negative regulator of insulin signaling in vitro and in vivo. Multiple lines of evidence support an important role of LMPTP in modulating glucose and lipid metabolism in obesity. Recent in vivo data obtained using antisense oligonucleotides showed that knockdown of LMPTP reverses insulin resistance and lipid abnormalities in obese mice. Thus LMPTP appears to be a promising drug target for the metabolic syndrome. We hypothesize that a specific small-molecule inhibitor of the LMPTP can be useful to prevent or treat the metabolic complication of obesity. Such an inhibitor would be widely applicable, both in helping to elucidate the biological role(s) of LMPTP and as a therapeutic in the treatment of the metabolic syndrome. In the present proposal we will screen the NIH chemical library for inhibitors of LMPTP, and generate a potent and selective probe that can be used in studies on mouse models of the metabolic syndrome.

Public Health Relevance

Reduced sensitivity of tissues to insulin is common in obese people, and is responsible for the development of lipid and glucose metabolism abnormalities (the metabolic syndrome), which significantly increase cardiovascular morbidity and mortality. This grant is focused on the LMPTP, a regulator of insulin action and a candidate drug target for treatment of the metabolic syndrome. Recent experiments in animals have provided proof-of-principle that LMPTP is a promising drug target in obesity. Our goal is to develop a specific small- molecule inhibitor of the LMPTP to prevent or treat the metabolic complication of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA033986-02
Application #
8416339
Study Section
Special Emphasis Panel (ZRG1-BST-F (50))
Program Officer
Singh, Hari
Project Start
2012-02-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$43,262
Indirect Cost
$19,012
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037