​The Maurice lab investigates the role that subcellular compartment-specific hydrolysis of cyclic nucleotide (cAMP and cGMP), by the cyclic nucleotide phosphodiesterases (PDEs), plays in promoting selective cyclic nucleotide-signaling in human arterial endothelial and smooth muscle cells. Since virtually all functions of these cell types are regulated by cyclic nucleotide-signaling systems, our studies may allow identification of novel therapeutic targets for management of multiple cardiovascular diseases, including atherosclerosis and restenosis, and in important vascular processes such as vasculogenesis and angiogenesis.

Plant-associated microorganisms alter the growth and development of their hosts in diverse ways. My research is aimed at understanding the mechanisms by which microbial effectors modulate host phenotype during both pathogenic and mutualistic host-microbe interactions. In this seminar, I will discuss novel screens employed to identify effector proteins of a bacterial plant pathogen (phytoplasma) and a fungal endosymbiont of roots (arbuscular mycorrhizal fungi) that act to modify host phenotype, leading to the discovery of novel microbial proteins that act to reprogram the host transcriptome. This research significantly advances current understanding of plant-microbe interactions, offering unprecedented insight into the mechanisms by which plant-associated microbes groom susceptible plants to promote colonization. 

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​The advent of CRISPR-Cas9 system provides an effective way to introduce targeted loss-of-function mutations in mammalian cells. CRISPR-Cas9 genetic screening enables the identification of cellular fitness genes that operate either globally (core fitness genes) or specifically within a particular genetic background or environmental context (context-specific fitness genes) at an unprecedented depth.  In tumors, this is the foundation for the concept of synthetic lethality as genes required in tumor cells but not in adjacent normal tissues should make ideal therapeutic targets with high effectiveness and minimal side effects. Towards this goal, we have developed a second-generation CRISPR guide RNA library of 176,500 guides targeting 17,661 human protein-coding genes. We used the library to screen five human cell lines to identify genes whose knockouts induced significant fitness defects. We further characterize novel fitness genes of unknown function and find that they all likely exist in protein complexes with other essential genes. Our screens accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. We also identified a surprising and specific dependency on mitochondrial activity, which strongly supports the idea that oxidative phosphorylation dependency – a clear exception to the Warburg effect – is a targetable weakness of some tumors. Our findings demonstrate that the CRISPR-Cas9 system fundamentally alters the landscape for systematic genetics in human cells through rigorous identification of cell line essential genes, affording a high-resolution view of the genetic vulnerabilities of a cell that may represent therapeutic opportunities in cancer.
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​Natural selection requires a mechanism of variation and a mechanism of selection that operates on that variation.  Reward-related or incentive learning is the acquisition by neutral stimuli of an increased ability to elicit approach and other responses.  It is similarly a selectionist process, variations in behavioral responses in specific environments being selected by their consequences.  The neural systems and molecular mechanisms underlying this selection are beginning to be understood.  Behavioral responses and specific environmental stimuli activate assemblies of neurons that project into a brain region, the striatum, that interfaces with motor output regions controlling behavioral responses.  When particular responses are made in the presence of particular stimuli, the cell assemblies they activate create a state of readiness in a subset of striatal synapsses by releasing glutamate that acts on receptors that alter calcium concentrations; these inputs lead to a wave of phosphorylation events in dendritic spines of postsynaptic neurons (targets include Kv4.2 channels, CaMKII, GluR1 subunits of AMPA receptors, ERK1/2, PP2A, DARPP-32).  If no rewarding stimulus is encountered, these post-synaptic events are quickly undone by a wave of phosphatase events (e.g., activation of PP2B, PP1, pThr75DARPP-32, STEP).  Neurons that use dopamine as their neurotransmitter project to this interface and play a critical role in reward-related learning.  Dopaminergic neurons have bursts of action potentials when an animal encounters a biologically important rewarding stimulus such as food, water, a mate or safety from danger.  The increase in dopamine concentration in its terminal regions acts via D1 receptors on the same dendritic spines as the glutamate inputs to initiate a series of events (cAMP, PKA, pThr34DARPP-32, CREB) in the target neurons that arrest the wave of phosphatase consequent to the glutamatergic input and thereby allow the wave of phosphorylation to endure (RSK2, Elk1, MSK1).  The enduring wave of phosphorylation in cooperation with phosphorylation events produced by the dopaminergic input act to produce changes in local proteins and new protein synthesis that serves to strengthen recently active glutamatergic synapses.  These modified synapses are the biological basis of reward-related learning.  As a result of this learning, specific environmental stimuli and the particular responses directed towards those stimuli acquire an increased ability to elicit approach and other responses in the future.
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