Ravi Iyengar

..Each lecture is 2 hours. After each set of lectures, there is a 2-hour discussion period during which students present an in-depth analysis of a primary literature article, selected in consultation with the lecturer...

..This new knowledge can drive drug discovery and shape precision medicine...

..The interface of the two fields will enable drug discovery for personalized medicine. Here we provide a perspective on the questions and approaches that drive the development of these new interrelated fields...

..The lecture concludes with a description of how models can be tested experimentally and modified when the details of the models and the resultant predictive behavior are not confirmed by experimentation...

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..quot; The lecture begins with a discussion of the crystal structure of rhodopsin and G protein subunits and then proceeds to describe the molecular mechanisms of receptor activation and the subsequent release of G proteins...

..A description of the lecture, along with a set of slides (http://stke.sciencemag.org/cgi/content/full/sigtrans;2005/270/tr4/DC1) used to present this information, is provided...

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..The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1)...

..In conclusion, HIV-1 induces VEGF and VEGFR2 expression in podocytes, and this may be a critical step in the pathogenesis of HIVAN...

..Thus, the biophysical properties of the plasma membrane can condense varying levels of signaling network activities into a single cohesive macroscopic cellular behavior...

..Free Sprouty then in turn inhibits growth factor signaling. Thus, here we present a novel mechanism of how G(o/i)-coupled receptors can inhibit growth factor signaling to MAPK...

..The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation...

..Key regulators of plasticity were highly connected nodes required for the formation of regulatory motifs, indicating the potential importance of such motifs in determining cellular choices between homeostasis and plasticity...

..Overall, this study demonstrated that G alpha(o/i)-coupled CB1R triggers neurite outgrowth in Neuro-2A through the activation of a signaling network containing two pathways that bifurcate at Src and converge at Stat3...

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..Components in the Science Signaling Connections Map are linked to Nature Molecule Pages. This interoperability provides ready access to detail that includes information about specific states for the nodes...

..We conclude that in HIV-infected podocytes, Nef, through the recruitment of DIP and p190RhoAGAP to Nef-Src complex, activates p190RhoAGAP and down-regulates RhoA activity...

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..These observations suggest that G(o/i)-coupled receptors, by stimulating the degradation of RGS20, can regulate how subsequent activation of the G(s) and G(i) pathways controls cellular cAMP levels, thus allowing for signal integration...

..The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/...

..These results provide a mechanism where multiple protein kinases and transcription factors interact to integrate signals from G protein-coupled and cytokine receptor to evoke neurite outgrowth in Neuro2A cells...

..The emergence of large-scale signaling networks provides an opportunity for topological statistical analysis while visualization of such networks represents a challenge...

..These results indicate that bifan motifs in cell signaling networks can contribute to signal processing capability both intrinsically and by enabling the functions of other regulatory motifs...

..These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1...

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..Disease-centered networks within the human interactome allow us to predict which drugs may produce a similar pathophysiology. Such predictions can be tested in animal models...

..Further, the recently discovered PFAHL motif was confirmed to bind and to be involved with stimulation of AC2 by Gβγ. These functional studies indicate that multiple regions of AC2 are involved in the interaction with Gβγ...

..We suggest that such mixed graphs will provide more accurate descriptions of functional cellular networks and their regulatory capabilities and aid in the development of large-scale predictive models of cellular behavior...

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..These mechanistic insights can provide a format for understanding how force and chemical signals together modulate cellular regulatory networks to control cell motility...

..Simple web-based visualization tools can allow for improved data presentation and collaboration. Researchers studying cell signaling would benefit from having the ability to embed dynamic cell signaling maps in web pages...

..The use of deterministic, stochastic, and hybrid models to represent cellular processes is reviewed, and an initial integrated approach for the development of large-scale predictive models of a mammalian cell is presented...

..Understanding interactions and changes in signal flow within the cell is important to our understanding of signaling networks as well as our ability to identify cellular targets for novel therapies to inhibit cancer progression...

..These results suggest a mechanism whereby synaptic stimulation, by signaling through the mTOR pathway, produces an increase in dendritic translational capacity that contributes to LTP maintenance...

..This allows rapid identification of biomarkers for side effect susceptibility. In this way, systems pharmacology will lead to not only newer and more effective therapies, but safer medications with fewer side effects...

..The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy...

..This integration of experimental approaches and computational modeling is expected to generate new knowledge that can help to identify marker sets to guide the diagnosis, monitor disease progression, and identify new therapeutic targets...

..This topology provides more dynamic stability in large networks...

..Different mathematical approaches that are currently used to model signaling networks are described, and future challenges including the need for databases as well as enhanced computing environments are discussed...

..We also analyze the role neurotransmitters, which stimulate Go/i to activate a complex signaling network controlling neurite outgrowth, play in regeneration after neuronal injury...

..These results are the first to indicate that the JXM domain of EGFR is a viable drug target for several cancer types...

..Disease-centered networks within the human interactome allow us to predict which drugs may produce a similar pathophysiology. Such predictions can be tested in animal models...

..Recent studies have combined the structural analyses with analysis of regulatory networks to make predictions about the therapeutic effects of drugs for complex diseases and possible off-target effects...

..We conclude that the emergence of ultrasensitivity from coupled first-order reactions provides a versatile mechanism for the design of biochemical switches...

..These initial observations allow for development of an integrated research methodology to identify general principles of the drug discovery process...

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..Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of existing medications...

..The integration of high-throughput experimental results and information from legacy literature is expected to produce computational models that would rapidly enhance our understanding of the detail workings of mammalian cells...

..Other binding regions may be arranged within the protein to impart specificity of recognition and thereby maintain overall contact between the partners during the conformational dynamics that occur in the signal-transfer process...

..We anticipate that such approaches will apply throughout the biomedical sciences and that courses such as the one described here will become a core requirement of many graduate programs in the biological and biomedical sciences...

..Finally, the modeling approach is expanded to describe how signaling networks might regulate cellular machines and evoke phenotypic behaviors...

..Thus, the G(alpha)o/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth...

..These results raise the possibility that sustained elevation of cAMP may have therapeutic value in the treatment of estrogen-resistant later stage breast cancers...

..This review describes the capability and limitations of the approaches used to study spatio-temporal dynamics of cell signalling components...

..It is posited that local translation at the synapse, in a self-sustaining manner, mediates the persistence of long-term changes despite constant turnover of the synaptic components...

..Thus, patterns of locally restricted signaling reaction systems can be considered an emergent property of the cell...

..We anticipate that, when appropriately populated, such a system will be useful for large-scale quantitative studies of cell-signaling networks and other cellular networks. SigPath is distributed under the GNU General Public License...

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..This is followed by a brief summary of some recent modelling successes and the state of future models...

..We conclude that Gq signaling promotes nuclear export and calpain-mediated degradation of beta-catenin, which therefore contributes to the inhibition of Wnt/beta-catenin pathway...

..These data suggest that Nef-induced activation of Stat3 and Ras-MAPK1,2 via Src-dependent pathways is responsible for podocyte proliferation and dedifferentiation, a characteristic finding in collapsing FSGS of HIVAN...

..This analysis provides initial insights into distribution of pathways in naturally evolving complex systems that have defined input-output relationships...

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..We propose how these methods could be integrated with creation and manipulation of mouse models of DS to advance our understanding of the perturbed cell signaling pathways in DS. This understanding could lead to potential therapeutics...

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..Drug-target networks can be used to identify multiple targets and to determine suitable combinations of drug targets or drugs. Thus, the discovery of new drug therapies for complex diseases may be greatly aided by systems biology...

..These cellular processes in turn regulate systemic functions such as embryonic development, gonadal development, learning and memory, and organismal homeostasis...

..These types of complex behavior from relatively simple networks highlight the necessity of using theoretical approaches in understanding higher order biological functions...

..From such analysis we hope to define the key criteria involved in determining the characteristics of microdomains of signaling molecules within the cell. ..

..We will use the filtration barrier of the kidney cortex as our model system. We will use a combination of mathematical models and engineering approaches to develop a 3D tissue assembly. ..

..It is anticipated that these studies will lead to the identification of key intracellular sites that are potential targets for therapeutic agents that have their effects by modulation of G protein signaling pathways. ..

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..From these studies we anticipate that we will develop a predictive understanding of how the cannabinoid and Galphao regulated signaling network triggers neurite extension. ..

..Understanding the relationship between intracellular organization and decision making in brain cells will allow us to identify new drug targets and develop new approaches to treat complex diseases. ..

..Such understanding could lead to new long acting therapeutic agents for many diseases. ..

..We anticipate that the proposed studies should provide new insights into how G protein coupling to other signal pathways can be used to evoke biological effects. ..