My long term goal is to become a leader in the field of Alzheimer's disease research. I plan to reach this objective by studying the changes in the microtubule-associated protein tau that lead to a decrease in its normal functions and increase its pathological ability to self-assemble into filaments found in Alzheimer's disease and many other neurodegenerative disorders. We hypothesize that changes in the phosphorylation state of tau alters its biochemical characteristics of microtubule binding and self- assembly. We propose to test this hypothesis by accomplishing the following specific aims: 1) We will determine the effects of phosphorylation events known to occur in Alzheimer's disease on the ability of' tau to form fibrils; 2) We will measure the effects of phosphorylation sites generated in Aim 1 on their interactions with microtubules and their ability to polymerize in the presence of microtubules; 3) We will determine whether phosphorylation events have differential effects on the fibril formation or microtubule binding of the six isoforms of the tau protein; 4) We will determine whether combining phosphorylation events in a single protein to generate a """"""""hyperphosphorylated"""""""" form of tau will lead to larger effects on tau's functional properties; and 5) We will use kinases that target tau protein in order to determine the effects of phosphate addition on its fibril formation and fibril stability both pre- and post-polymerization. The first step in reaching this objective was the funding of an R01 (AG022428) to study these Aims using biochemical techniques such as dynamic light scattering, right angle laser light scattering, fluorescence assays, and electron microscopy. In order to move this research to a nationally prominent level, I am seeking the Independent Scientist Award in order to obtain time off from teaching to provide the necessary training to the relatively inexperienced workers in the laboratory. Specifically, I hope to provide training in the proper execution of the experiments, responsible conduct in the recording of the data, and assistance in the interpretation of the data. I feel that this time will greatly increase the productivity in the laboratory and enhance the development of my career. ? ? ?
