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HUJI

Hebrew University of Jerusalem
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550 Projects, page 1 of 110
  • Funder: European Commission Project Code: 227634
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  • Funder: European Commission Project Code: 852387
    Overall Budget: 1,499,880 EURFunder Contribution: 1,499,880 EUR

    Time underlies each and every activity and perception. And yet our knowledge about time perception remains limited. It is hindered by a division between psychological and behavioral findings on the one hand, and neuroscience findings on the other hand. The former rarely address biological constraints, while the latter rarely informs a unified theory for timing. Theories on time perception have centred on the modular nature of time perception. Is time sensed through the operation of central mechanisms serving all sensory and motor systems? Or is time sensed locally, within different sensory and motor systems? TIMECODE entertains a third possibility for time perception in the brain and overcomes the gap between psychological theories and physiological manifestations of time by assuming a hierarchy of time that entails both a local level of analysis and a domain-general level of analysis. I identify three dimensions that need to be investigated in order to substantiate this possibility. First, local representations of time need to be identified within sensory (and motor) systems. Second, network dynamics that support the propagation of such representations need to be investigated. Brain rhythms play an important role in both local and inter-areal computations. Thus, the role of brain rhythms will be assessed for both levels of analysis. Finally, a brain-wide assessment of selectivity to time needs to be explored. TIMECODE investigates the initial local code for time, global code for time, and the inter-areal dynamics between them by combining human physiology (invasive and non-invasive) with illusions of time perception (in behavior). It investigates brain-wide selectivity to time by applying computational tools to intracranial data from human and non-human primates. Combining behavioral, systems neuroscience, and computational tools is imperative in order to offer a far-reaching theory of timing in the brain and allow a leap forward in understanding cognition.

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  • Funder: European Commission Project Code: 101100628
    Funder Contribution: 150,000 EUR

    Obesity is a catalyst for numerous conditions; the most notable is non-alcoholic fatty liver disease (NAFLD), for which currently no drug therapy has been approved by the FDA and EMA for its treatment. The endocannabinoid (eCB) system triggers the development of obesity and its related comorbidities, specifically NAFLD. eCBs, via activating the cannabinoid-1 receptors (CB1Rs) in the liver, increase hepatic glucose production, insulin resistance, and de novo lipogenesis, and decrease fatty acid oxidation. Accordingly, globally-acting CB1R blockers improve these parameters both in rodents and humans. However, owing to their neuropsychiatric side effects, they were withdrawn from the market and are no longer available for clinical use. NANOFLD aims to revive their clinical development and testing by utilizing an innovative nanometric drug delivery system for the hepatic targeting of globally-acting CB1R blockers for treating NAFLD. In the framework of my ERC-StG grant, CaNanoBinoids, my team successfully encapsulated the first-in-class CB1R blocker, rimonabant, in nanoparticles (NPs), tested their stability, efficacy, and potency, and demonstrated their therapeutic potential in ameliorating NAFLD, insulin resistance, and dyslipidemia in mice. To further translate our findings into clinical practice, the present PoC application builds on and expands this avenue of research by achieving several necessary steps including biodistribution, hepatic cellular fate, and PK studies of our novel nanometric drug delivery system. Importantly, we have secured the IP, conducted a specific market assessment, targeted regulatory constraints, implemented a business development plan, consulted with professionals in the field, and developed contacts with industry. When this project is completed, we expect to have introduced a unique innovation to treat NAFLD and its metabolic abnormalities, further promoting the idea to clinically test CB1R blockers encapsulated in NPs against NAFLD.

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  • Funder: European Commission Project Code: 203994
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  • Funder: European Commission Project Code: 947907
    Overall Budget: 1,500,000 EURFunder Contribution: 1,500,000 EUR

    Adaptation to recurring environmental challenges (food availability, seasonal rhythms etc.) is a mainstay of physiology. As such, mammals are exquisitely fitted to tolerate frequent bouts of fasting owing to hepatic production of fuels (glucose, ketones). Indeed, studies show significant health benefits of intermittent fasting. Due to the reliance of the fasting response on chromatin and transcriptional regulation, I hypothesize that mammals adapt to recurring fasting by sensitizing transcriptional programs and maximizing future responses, thereby increasing survival. I plan to uncover transcriptional mechanisms of ‘fasting memory’ that mediate the health benefits of recurrent fasting. I will profile the hepatic transcriptome and genome-wide chromatin landscape of intermittently-fasted mice to discover the mediators of such memory. I will evaluate three plausible mechanisms: (1) Enhancer priming whereby the DNA regulatory elements dictating gene expression are kept in a primed state between fasting episodes. (2) Promoter priming in which RNA polymerase is paused at gene bodies during feeding and rapidly released upon re-fasting. (3) Transcriptional cascades whereby genes induced in the previous fasting bout are active in the next one, directing a second wave of gene expression. The molecular mechanisms mediating memory will be examined in a series of gain/loss of function experiments targeting various components of transcriptional regulation (transcription factors, RNA polymerase, histone and DNA modifications etc.). Both the notion of fasting memory and the cellular mechanisms driving it are supported by preliminary results. The concept raised here has the potential to unravel a fundamental homeostatic response and significantly advance fasting research. More broadly, such a discovery would reshape our view of transcriptional regulation as a cellular adaptation mechanism to recurring challenges and of physiological habituation to the environment.

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