Mollie  Meffert, MD, PhD

Assistant Professor

Telephone Number: 410-502-2570

Lab Phone: 410-502-2571

Fax Number:   410-955-5759

Johns Hopkins University

School of Medicine

725 North Wolfe St.

Baltimore, MD 21205

Room: (Lab) 420, 413 Physiology Building

(Office) 421 Physiology

     General principles of adaptive regulation which interest the lab include the modulation of gene expression by synaptic signaling, mechanisms for transducing signals between the synapse and the nucleus, how stimuli are differentiated to generate growth and survival versus apoptotic responses, the interaction and regulation of transcription factors to generate distinct and overlapping functions, and the influence of plastic changes in gene expression on behavior. The neuronal function of the Nuclear Factor kappa B (NF-kB) transcription factor is initially being used as a model system to approach these questions.

     NF-kB is held latent in the cytoplasm of most cells by the inhibitory IkB proteins. Activating stimuli release NF-kB which moves to the nucleus where it modulates gene transcription after binding to its cognate DNA motifs. The function of the NF-kB family of transcription factors has become a classical paradigm in modern cell biology. Not only do we know most members of this family, we have also gained an understanding of their three dimensional structures, their physiological functions, and signaling pathways leading to NF-kB activation. The groundwork and available tools have now primed this field for investigation in the CNS. The study of NF-kB provides a good vantage point from which to explore transcriptional regulation in neurons. Given the prominence of NF-kB in apoptotic pathways and regulation of the immune response, it is highly likely that NF-kB will be a key player in CNS diseases. Functions for NF-kB in the healthy CNS have also been discovered.

     We have demonstrated that NF-kB is present at synapses and that upon treatment with physiological stimuli, activated NF-kB can translocate from distal processes to the nucleus. In addition, we have conducted behavioral studies using mice lacking the p65 subunit of NF-kB. These studies have revealed a role for NF-kB in spatial learning. A central focus of the lab is to understand the signaling pathways regulating NF-kB in this system and how NF-kB exerts its function.

Questions which are of immediate interest to the lab include:

•What are the components of the synaptic NF-kB complex responsible for activation and nuclear translocation in neurons?

•Are the roles of NF-kB different in neurons versus glia?

•Can we differentiate the physiologic and behavioral functions of NF-kB through the creation of tissue-specific and inducible knock-out mice?

•What gene programs are activated by NF-kB in the CNS?