Genomic instability syndromes: Ataxia-telangiectasia Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive cerebellar ataxia, oculo-facial telangiectases (dilated blood vessels) immunodeficiency, premature aging, gonadal dysgenesis, extreme radiosensitivity, genomic instability and high incidence of lymphoreticular malignancies. A-T is a prime example of a genomic instability syndrome caused by defective DNA damage response. A-T is caused by loss or inactivation of the ATM protein, a large nuclear serine/threonine kinase with a carboxy terminal domain containing PI3 kinase motifs. ATM belongs to a conserved family of large proteins that share the PI3 kinase-like domain and are involved in various stress responses, most notably the DNA damage response. ATM mediates the activation of a network of signaling pathways that are activated by DNA double strand breaks (DSBs). The ATM-mediated response includes the cell cycle checkpoints, and numerous other pathways related to various aspects of cellular metabolism. Atm-eficient mice recapitulate many features of the human A-T phenotype and display growth retardation, infertility, predisposition to thymic lymphomas, and acute sensitivity to ionizing radiation (IR), but only mild neurological deficits which are noted meremly in certain strains of Atm-/- animals. These mice thus provide a model for exploring most of the features of the A-T phenotype. In an effort to dissect the A-T phenotype, we augment specific features of the human disease by generating mouse strains that combine Atm deficiency with dysfunction of other proteins. Using these mice, we focus on a study of the molecular mechanisms of the DNA damage response that may lead to cerebellar pathology or to increased cancer predisposition.
The molecular mechanism of optic nerve regeneration: Millions of people throughout the world become blind as a result of a devastating disease or trauma. The protection of optic nerve axons from death until the acute phase of the assault is over will be of great benefit for the recovery of sight. Recent approaches in animal models, including our work, indicate that in principle, retinal neurons can be protected from secondary death. Furthermore, the option of replacing the damaged eye with a donor eye, human eye transplantation, could be the victory over all the devastating factors mentioned above. However, even in the case of transplantation, the severed axons of the RGCs, which form the optic nerve, must regenerate and reconnect with target areas in order to regain vision. Thus, an understanding of the cellular and molecular events that accompany optic nerve diseases and the development of protective and regenerative therapies are instrumental in the achievement of these goals.