Request for Funding
Medical Student Research Fellowship for Summer 2011
All descriptions must contain enough detail to permit an assessment of the problem that is to be addressed and the methodologies that are to be employed. Please be careful to outline the role that the student will play in the project that is described. Please ensure that all relevant approval numbers (IRB, IACUC) are provided.
Mentor: Joseph P. Albanesi
Mail Code: 9041
Phone number: 214 645 6119
Project title: Mechanisms of Arc-membrane interactions
Human subjects IRB approved project number (where applicable):not applicable
Animal subjects IRB approved project number (where applicable):not applicable
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Brief Description of Project: Arc (Activity-regulated cytoskeleton-associated protein) is an Immediate Early gene product induced in a variety of behavioral and leaning paradigms. It is synthesized locally in neuronal dendrites in response to activation of metabotropic glutamate receptors, and in this context has been associated with reduction in synaptic strength. Emerging evidence indicates that Arc facilitates internalization of AMPA-type glutamate receptors from the surface of dendritic spines, and it has been shown to interact directly with two elements of the endocytic machinery, dynamin and endophilin, both of which are studied in our laboratory. Abnormally high levels of Arc have been linked to cognitive disorders, including Fragile-X and Angelman’s syndromes.
We recently showed that Arc stimulates the GTPase activity of dynamin, which is essential for receptor-mediated endocytosis. We also showed that Arc binds directly to membranes, suggesting that it may serve as a scaffold for dynamin assembly around the necks of nascent endocytic vesicles. Because Arc is a highly acidic, soluble protein and lacks an obvious membrane interaction motif, we sought to understand the molecular basis of its interaction with lipids, and observed that Arc undergoes palmitoylation in cells. The student will perform inhibitor-based studies to determine whether palmitoylation is critical for targeting of Arc to membranes of cultured cells, and will use a variation of two-color TIRF (Total Internal Reflection Fluorescence) microscopy to determine if this modification enhances the recruitment of dynamin and/or endophilin to the plasma membrane of living cells. She will also attempt to identify the pamitoylation sites by mutational analysis, with the long-term goal (beyond the scope of this summer project) of introducing unpalmitoylatable mutants into mice and determining the consequences of this intervention on behavior and memory consolidation.
Previous Research Activities or Publications with Medical Students: none