We are interested in the molecular mechanisms that underlie neuronal growth, development, and synaptogenesis. We are also developing chemical approaches for studying signal transduction.

MOLECULAR NEUROSCIENCE

We are interested in understanding how axons of developing vertebrate neurons locate, and form synapses with, appropriate target cells. These functions are performed by the growth cone, a structure at the tip of developing or regenerating axons that has highly specialized chemotactic and motile functions. Growth cones function as semiautonomous outposts of neurons, with the capacity to detect and respond to extracellular signals, including the ability to respond to signaling molecules by regulating protein translation. We have found that mammalian growth cones require protein synthesis in order to sense and respond to guidance cues such as netrin-1 and semaphorin-3A. Using a variety of techniques including single cell PCR and in situ hybridization we have identified novel mRNAs that are enriched in growth cones and mediate their responses triggered by extracellular cues. We are investigating how local mRNA translation mediates the actions of growth cones and the signaling molecules that couple receptor activation to protein translation.

Abnormalities of axonal growth and synaptogenesis have been implicated in certain forms of autism and mental retardation. A focus of our work is determining the relationship between aberrant growth cone regulation of protein translation and these disorders. Since growth cones transduce signals that prevent axonal regeneration, this work will also contribute towards developing therapeutic strategies to promote axonal regeneration following neuronal injury or degeneration.

CHEMICAL BIOLOGY

We are interested in applying chemical synthesis to problems in cell signaling that cannot be answered using current methodologies. A major focus of our efforts is the development and application of mass spectrometry (MS) to perform proteome-wide screens to identify properties and functions of proteins. We have developed approaches to detect protein S-nitrosylation, a post-translational modification of cysteine residues, on a proteome-wide scale. We are developing novel mass spectrometry-based methods that employ chemical manipulations of proteins and peptides to identify physiological substrates of proteases using isotope-coded tagging approaches and multidimensional liquid chromatography-MS/MS.

We are also using chemical library approaches to develop small molecules that can serve as probes of biological signaling pathways. We are synthesizing and screening libraries to generate novel nitric oxide donors (NO) that have are capable of tissue or disease-specific NO release. We are also developing small molecule scavengers of nitric oxide that have the potential to deplete NO in specific subcellular compartments. Other projects include applying protein microarrays for high-throughput screening solution-phase small molecule peptidomimetic libraries.

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Jaffrey Lab Website: Jaffrey Lab