This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ataxia-Telangiectasia (A-T) is an inherited disorder that causes neurodegeneration, immunodeficiency, genomic instability, increased sensitivity to ionizing radiation, and a predisposition to lymphoreticular malignancy . A-T is caused by mutations in the ATM (A-T mutated) gene, encoding a serine and threonine kinase protein (ATM) that has roles in signaling cell-cycle arrest and DNA repair after double-stranded breaks in DNA . The mechanisms underlying the apoptotic death of lymphocytes and neurons are largely unknown. It has been hypothesized that A-T cells may have an inability to counteract the damaging effects of reactive oxygen species (ROS) on DNA. In addition, A-T patients may have increased production of ROS due, in part, to chronic/recurrent infections. Indeed, increased levels of oxidative damage to lipids and DNA have been detected in humans and mice expressing loss of function mutations of ATM. Lymphoblastoid cell lines with A-T mutations have constitutive activation of pathways that respond to genotoxic stress with elevated basal levels of p53, p21, phosphoserine-15 p53, and phosphotyrosine-15 cdc2. The levels of each of these stress proteins decreases when cells are cultured in the presence of the anti-oxidant, alpha-lipoic acid. There are several potential ways to counteract the effects of oxidative stress. One approach is to use anti-oxidants. One such compound, alpha-lipoic acid, can directly scavage reactive oxygen species (ROS), stimulate the synthesis of glutathrione which is itself an ROS scavenger, and regenerate other anti-oxidants such as vitamins C and E. In fact, when A-T cells are cultured with alpha-lipoic acid, the cellular levels of stress proteins decrease. Another approach is to block the consequences of oxidative stress. Protein ADP-ribosylation by poly ADP ribose polymerase (PARP) is thought to play an important role in DNA repair after oxidative damage. However, PARP activationn can cause rapid depletion of cellular NAD+ and ATP with subsquent abnormalities in cell growth and/or apoptosis. PARP inhibitors may be able to minimize these secondary effects. We propose a double-blind, placebo-controlled pilot study of an anti-oxidant (alpha-lipoic acid) and a PARP inhibitor (nicotinamide) in adolescents and adults (> 12 years old) with A-T. The primary outcome measures will be changes in levels of oxidative damage to lipids and DNA. Secondary outcome measures will be changes in lymphocyte count and neurologic function, and safety.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000052-45
Application #
7378905
Study Section
Special Emphasis Panel (ZRR1-CR-1 (01))
Project Start
2005-12-01
Project End
2006-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
45
Fiscal Year
2006
Total Cost
$18,631
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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