Research Awards
Genevieve Laforet, M.D., Ph.D.
University of Massachusetts
HDAC Activation in RTT
$100,000
Lay Progress Report (August 2005)
Our research focuses on the underlying molecular mechanisms leading to abnormal brain development in Rett syndrome (RTT), with an eye toward correcting these mechanisms using drug therapy. RTT is caused by mutations in MeCP2, a protein involved in control of gene expression. We use mouse models that are deficient in MeCP2, as well as brain cells (neurons) isolated from these animals, to investigate the disruptions in cell function and gene expression associated with MeCP2 impairment. MeCP2 normally recruits other proteins called histone deacetylases (HDACs) that chemically modify histones, the protein scaffolds that house DNA in the nucleus. The resultant histone modifications alter DNA-histone interactions and make genes in the DNA less accessible for expression. We have demonstrated that MeCP2 deficiency makes it harder for HDACs to make these important modifications, as reflected by reduced levels of histone deacetylation in MeCP2-deficient embryonic neurons in culture. This in turn perturbs expression of developmentally important genes such as Dlx5 and Sgce in embryonic neurons. We have shown that drugs such as theophylline and anacardic acid can restore the proper balance of chemical modifications that are disrupted when MeCP2 and HDAC activity is disrupted, making them possible therapeutic candidates for RTT. In addition to work with cultured cells, we are also testing MeCP2 deficient mice to characterize their neurological and behavioral abnormalities, in order to devise practical experimental paradigms to evaluate drug treatments in RTT animal models. Based on these studies, we are beginning treatment trials to evaluate whether drugs like theophylline that modify HDAC activity can prevent or reduce symptoms in MeCP2 deficient mice. Our ultimate goal is to determine whether drugs that act on histone-modifying enzymes are useful therapeutic agents for correcting abnormal gene expression and restoring normal neuronal development in RTT animal models and patients.
Genevieve Laforet, M.D., Ph.D.University of Massachusetts
HDAC Activation in RTT
$100,000
Lay Progress Report (August 2005)
Our research focuses on the underlying molecular mechanisms leading to abnormal brain development in Rett syndrome (RTT), with an eye toward correcting these mechanisms using drug therapy. RTT is caused by mutations in MeCP2, a protein involved in control of gene expression. We use mouse models that are deficient in MeCP2, as well as brain cells (neurons) isolated from these animals, to investigate the disruptions in cell function and gene expression associated with MeCP2 impairment. MeCP2 normally recruits other proteins called histone deacetylases (HDACs) that chemically modify histones, the protein scaffolds that house DNA in the nucleus. The resultant histone modifications alter DNA-histone interactions and make genes in the DNA less accessible for expression. We have demonstrated that MeCP2 deficiency makes it harder for HDACs to make these important modifications, as reflected by reduced levels of histone deacetylation in MeCP2-deficient embryonic neurons in culture. This in turn perturbs expression of developmentally important genes such as Dlx5 and Sgce in embryonic neurons. We have shown that drugs such as theophylline and anacardic acid can restore the proper balance of chemical modifications that are disrupted when MeCP2 and HDAC activity is disrupted, making them possible therapeutic candidates for RTT. In addition to work with cultured cells, we are also testing MeCP2 deficient mice to characterize their neurological and behavioral abnormalities, in order to devise practical experimental paradigms to evaluate drug treatments in RTT animal models. Based on these studies, we are beginning treatment trials to evaluate whether drugs like theophylline that modify HDAC activity can prevent or reduce symptoms in MeCP2 deficient mice. Our ultimate goal is to determine whether drugs that act on histone-modifying enzymes are useful therapeutic agents for correcting abnormal gene expression and restoring normal neuronal development in RTT animal models and patients.