PROJECT SUMMARY (See instructions): At our proposed U54 center, we will continue to conduct epigenomic analysis in cancer. While the focus of the previous award was on epigenetic processes associated with neoplastic transformation of normal cells. In this competing application, we will move a step forward to study epigenetic changes in prostate, breast, and ovarian cancer cells progressing to an aggressive phenotype, i.e., hormone-Zchemo-resistance.

Alcohol binge drinking is associated with dangerous levels of intoxication that are costly to both the individual and society. NIAAA (2004) and others have defined a 'binge' as a drinking episode that produces a blood alcohol concentration of e .08 percent, which typically corresponds to five drinks for men and four drinks for women consumed within 2 hours. Most of what is known about binge drinking is based on studies of college students, however, most binge drinkers are older adults.

This project is an opportunity to identify biological mechanisms underlying binge drinking and their relationship to individual differences in the capacity to reduce drinking. We propose to characterize serotonin transporter (SERT) function using an immortalized human lymphoblastoid cell line (LCL) model among Binge and Non-Binge drinking adults recruited from R01-AA014988.

The NIA Interventions Testing Program represents a multi-site translational research program to evaluate agents hypothesized to extend mouse lifespan by retardation of aging or postponement of late life diseases.

Microhomology-mediated end joining (MMEJ) repairs DNA breaks by annealing 2-20 bp of flanking microhomology (MH), yielding repair products with deletions of MH and inter-MH sequences. MMEJ is thus a highly error prone repair mechanism with a strong propensity to lead to chromosomal translocations and cancer-causing mutations. Accordingly, the breakpoint junctions of many oncogenic chromosomal translocations feature MH, underscoring the importance of this mechanism for the development chromosome instability and carcinogenesis.

This competing continuation of K05DA17918 is submitted in response to PA-09-076 and requests 5additional years of support to provide protected time for the PI to continue a successful preclinicalresearch program on the behavioral pharmacology of opioids and other drugs and to mentor studentsand other young investigators in the area of drug abuse.

This proposal is a competitive renewal of R01NS045879 'Stroke Imaging of Conscious Rats.' In the previous grant cycle, we reported over two dozen peer-reviewed publications and leveraged multiple foundation grants to expand stroke research. Stroke remains to be the third leading cause of death and the leading cause of long-term disability.

Ion channel currents are the fundamental units of electrical activity in most organisms. In our nervous system, K+ and Ca2+ channels are critical, and their regulation provides a way to directly control neuronal excitability and release of neurotransmitter (NT) at synapses. The modulations are crucial to basic nervous function and their understanding should contribute to novel modes of medical interventions for a range of disorders involving the brain, nerves and muscles.

The proposed work innovatively addresses serious and long-standing limitations in the evidence supporting the standard relapse model. The important role of the standard model both in pre-clinical research into relapse and in clinical treatments to prevent relapse make it important to strongly test the assumptions of the standard model. This work could result in a strong validation of the standard model and improved animal models for developing medications designed to prevent relapse and craving.

The hallmark of myelinated axons is their organization into molecularly distinct domains, a pre-requisite for the rapid propagation of actionpotentials. The paranodal domains establish the axo-glial septate junctions (AGSJs) through interactions involving axonal Contactin-associated protein (Caspr), Contactin (Cont), and glial Neurofascin NF155. The nodal domain is organized by neuronal NF186, voltage gated sodium (Nav) channels, and Ankyrin G (AnkG), a cytoskeletal adaptor protein.