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Negri, Joseph

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Negri

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Joseph

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Negri, Joseph
Author's Publications: search.filters.isAuthorOfPublication.4a91f6cc-ba15-4fbb-9bea-dd9900518b56

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    Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability
    (Elsevier, 2017) Muratore, Christina; Zhou, Constance; Liao, Meichen; Fernandez, Marty; Taylor, Walter M.; Lagomarsino, Valentina N.; Pearse, Richard; Rice, Heather C.; Negri, Joseph; He, Amy; Srikanth, Priya; Callahan, Dana; Shin, Taehwan; Zhou, Monica; Bennett, David A.; Noggle, Scott; Love, J. Christopher; Selkoe, Dennis; Young-Pearse, Tracy
    Summary Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aβ, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aβ plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aβ and the responsiveness of TAU to Aβ are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.
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    Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor
    (American Chemical Society, 2012) Dockendorff, Chris; VerPlank, Lynn; Dilks, James R.; Gunnink, Susanna F.; Palmer, Michelle; MacPherson, Lawrence; Aisiku, Omozuanvbo Reginald; Smith, Daniel A.; Dowal, Louisa; Schreiber, Stuart; Flaumenhaft, Robert; Negri, Joseph
    A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure–activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile.
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    A Chemical Screen Probing the Relationship between Mitochondrial Content and Cell Size
    (Public Library of Science, 2012) Kitami, Toshimori; Logan, David J.; Negri, Joseph; Hasaka, Thomas; Tolliday, Nicola J.; Carpenter, Anne E.; Spiegelman, Bruce; Mootha, Vamsi
    The cellular content of mitochondria changes dynamically during development and in response to external stimuli, but the underlying mechanisms remain obscure. To systematically identify molecular probes and pathways that control mitochondrial abundance, we developed a high-throughput imaging assay that tracks both the per cell mitochondrial content and the cell size in confluent human umbilical vein endothelial cells. We screened 28,786 small molecules and observed that hundreds of small molecules are capable of increasing or decreasing the cellular content of mitochondria in a manner proportionate to cell size, revealing stereotyped control of these parameters. However, only a handful of compounds dissociate this relationship. We focus on one such compound, BRD6897, and demonstrate through secondary assays that it increases the cellular content of mitochondria as evidenced by fluorescence microscopy, mitochondrial protein content, and respiration, even after rigorous correction for cell size, cell volume, or total protein content. BRD6897 increases uncoupled respiration 1.6-fold in two different, non-dividing cell types. Based on electron microscopy, BRD6897 does not alter the percent of cytoplasmic area occupied by mitochondria, but instead, induces a striking increase in the electron density of existing mitochondria. The mechanism is independent of known transcriptional programs and is likely to be related to a blockade in the turnover of mitochondrial proteins. At present the molecular target of BRD6897 remains to be elucidated, but if identified, could reveal an important additional mechanism that governs mitochondrial biogenesis and turnover.