Lukasz J Bugaj

University of California, Berkeley, Berkeley, California, United States

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Publications (7)70.07 Total impact

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    ABSTRACT: Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.
    Oncotarget 05/2015; 6(14). DOI:10.18632/oncotarget.3851 · 6.36 Impact Factor
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    L J Bugaj · D P Spelke · C K Mesuda · M Varedi · R S Kane · D V Schaffer ·
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    ABSTRACT: Transmembrane receptors are the predominant conduit through which cells sense and transduce extracellular information into intracellular biochemical signals. Current methods to control and study receptor function, however, suffer from poor resolution in space and time and often employ receptor overexpression, which can introduce experimental artefacts. We report a genetically encoded approach, termed Clustering Indirectly using Cryptochrome 2 (CLICR), for spatiotemporal control over endogenous transmembrane receptor activation, enabled through the optical regulation of target receptor clustering and downstream signalling using noncovalent interactions with engineered Arabidopsis Cryptochrome 2 (Cry2). CLICR offers a modular platform to enable photocontrol of the clustering of diverse transmembrane receptors including fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and integrins in multiple cell types including neural stem cells. Furthermore, light-inducible manipulation of endogenous receptor tyrosine kinase (RTK) activity can modulate cell polarity and establish phototaxis in fibroblasts. The resulting spatiotemporal control over cellular signalling represents a powerful new optogenetic framework for investigating and controlling cell function and fate.
    Nature Communications 04/2015; 6:6898. DOI:10.1038/ncomms7898 · 11.47 Impact Factor
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    ABSTRACT: Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, though evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone Morphogenetic Protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline. This article is protected by copyright. All rights reserved. © 2014 AlphaMed Press.
    Stem Cells 12/2014; 33(5). DOI:10.1002/stem.1943 · 6.52 Impact Factor

  • 247th National Spring Meeting of the American-Chemical-Society (ACS); 03/2014
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    ABSTRACT: A genetically encoded optogenetic system was constructed that activates mRNA translation in mammalian cells in response to light. Blue light induces the reconstitution of an RNA binding domain and a translation initiation domain, thereby activating target mRNA translation downstream of the binding sites.
    Chemical Communications 08/2013; 49(75). DOI:10.1039/c3cc44866e · 6.83 Impact Factor
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    ABSTRACT: We report an optogenetic method based on Arabidopsis thaliana cryptochrome 2 for rapid and reversible protein oligomerization in response to blue light. We demonstrated its utility by photoactivating the β-catenin pathway, achieving a transcriptional response higher than that obtained with the natural ligand Wnt3a. We also demonstrated the modularity of this approach by photoactivating RhoA with high spatiotemporal resolution, thereby suggesting a previously unknown mode of activation for this Rho GTPase.
    Nature Methods 02/2013; 10(3). DOI:10.1038/nmeth.2360 · 32.07 Impact Factor
  • Lukasz J Bugaj · David V Schaffer ·
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    ABSTRACT: Recent advances in synthetic biology have created genetic tools with the potential to enhance the specificity, dynamic control, efficacy, and safety of medical treatments. Interfacing these genetic devices with human patients may thus bring about more efficient treatments or entirely new solutions to presently intractable maladies. Here we review engineered circuits with clinical potential and discuss their design, implementation, and validation.
    Current opinion in chemical biology 05/2012; 16(3-4):355-61. DOI:10.1016/j.cbpa.2012.04.009 · 6.81 Impact Factor