Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies availablefor the treatment of solid tumors. However, their utility is compromised by innate and acquired drugresistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumventmultiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratorieshave effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrowtherapeutic window.

Alzheimer's disease (AD) is a profoundly debilitating neurodegenerative disorder without effective treatment or determinative antemortem diagnostics. Improvements in diagnostic and treatment options will require a better understanding of the biological processes that drive AD onset and progression. The prevailing model to explain AD pathogenesis holds that neuronal degeneration and clinical demise are precipitated by the gradual accumulation, in brain centers controlling memory and cognition, of amyloid-? (A?) peptide, a catabolite of the transmembrane Amyloid Precursor Protein (APP).

This application in response to PA-11-184 is the first competing continuation of a new program entitled 'Training in drug abuse research: behavior and neurobiology' that provides research training and career development activities for postdoctoral fellows who aspire to careers in the area of drug addiction. In its first 4 years the Program has grown from 2 to 5 training positions, plus 1 additional position supported by UTHSCSA for a total of 6.

The recent reports that scopolamine has antidepressant effects in humans has raised the hope that this antimuscarinic drug represents an improvement over the serotonergic and noradrenergic reuptake blockers that have formed the basis for antidepressant medication for decades. Scopolamine's effects had a rapid onset of action, and were quite long lasting, giving them considerable advantage over previous medications.