This month we are highlighting two awards. The first, awarded to Dr. Alexei Degterev, Associate Professor of Developmental, Molecular & Chemical Biology, is his National Institutes of Health funded project titled ‘Targeting RIPK3 in Age-Related Inflammation and Injury.’ The second, awarded to Daniel Kuchma, Professor of Civil and Environmental Engineering, is a National Science Foundation funded project titled ‘Planning Grant: Engineering Research Center for Offshore Wind Energy Center for Infrastructure Resilience, Control, Innovation, and Transmission (OWE-CIRCIT).’ Please see the abstracts for these projects below.
PI: Alexei Degterev Funder: NIH Title: Targeting RIPK3 in Age-Related Inflammation and Injury Abstract: Human aging is accompanied by a range of progressive chronic diseases with inflammatory etiology (e.g., atherosclerosis and TNF-α-driven pathologies such as rheumatoid arthritis), as well as by elevated acute inflammatory responses, such as upon infection by influenza virus. These conditions remain in clear need of new therapeutic interventions. Recent evidence from our labs and other groups has revealed that an as-yet unexploited kinase, RIPK3, drives disease progression in settings of both chronic and acute inflammation, including in each of the examples mentioned above. RIPK3 is the central mediator of a highly pro-inflammatory form of cell death termed `necroptosis', or programmed necrosis. In atherosclerosis and TNF-α-mediated pathologies (such as rheumatoid arthritis, and ulcerative colitis), RIPK3-initiated necroptosis mediates release of danger-associated molecular patterns that amplify inflammation and drive disease progression. During acute influenza A virus (IAV) infection, RIPK3-mediated necroptosis underlies necrotic lung damage, which is an established instigator of two major morbidities in the elderly – viral pneumonia and acute respiratory distress syndrome (ARDS). Thus, RIPK3 is a very attractive new molecular target for multiple age-related pathologies. Curiously, given how important a therapeutic target RIPK3 potentially is, no selective RIPK3 inhibitors are in clinical use or ever been advanced into clinical trials. We now have developed a new structural class of RIPK3 inhibitors, which we call the UH15 series, and which are based on a pyrido[2,3-d]pyrimidine scaffold that targets both the ATP- as well as the allosteric Glu-out pockets of the kinase. Our preliminary findings reveal that UH15 analogs, after just one round of optimization, are already more potent than current RIPK3 blockers. These exciting results highlight the immediate translational potential of the UH15 series for a variety of chronic and acute inflammatory diseases of high relevance to the elderly. As no chemical probes exist to validate this novel biological target, RIPK3, in vivo, the immediate goals of our proposal are to iteratively optimize UH15 based compounds for RIPK3 blockade in vivo (Aim 1) and to use these chemical probes to directly assess the therapeutic efficacy of targeting RIPK3 kinase in vivo in mouse models of age-related chronic and acute inflammatory conditions, including atherosclerosis and TNF-driven pathology (Aim 2), and influenza virus- triggered morbidities (Aim 3).
PIs: Daniel Kuchma (PI), Alison Bates (Co-I), Sanjay Arwade (Co-PI), Aleksandar Stankovic (Co-PI), Paras Mandal (Co-PI) Funder: NSF Title: Planning Grant: Engineering Research Center for Offshore Wind Energy Center for Infrastructure Resilience, Control, Innovation, and Transmission (OWE-CIRCIT) Abstract: The Offshore Wind Energy (OWE) industry in Europe is booming, and has reduced electricity generation costs to less than $0.10 per kWh. The U.S. OWE resource is enormous, and could provide 10-20 times the national need for electricity. The U.S. is just starting to develop this resource, does not yet have an industrial supply chain for OWE, and there are unique U.S. challenges because of hurricanes, complex seabed conditions, and grid integration. In order to address these challenges, and to design resilient and cost-effective heavy OWE infrastructure (e.g., structures, transmission system), a convergent approach is needed. Failure for the U.S. to take this approach, to plan accordingly, to maximize continuous learning, and to take disruption actions when needed, would be a hugely missed opportunity for society to benefit from the breadth of U.S. expertise and knowhow, and to make technological advancements that have broad applications.
This ERC planning grant project will bring together those with relevant expertise in OWE from several engineering disciplines, fields of science, the national laboratories, state and federal resource management agencies, industrial stakeholders, and developers; as well as those from affected coastal communities. This group will design a data-driven multi-disciplinary system-level framework that identifies where advances are needed to build a resilient infrastructure (blades, turbine, support structure, transmission grid, standards, and models) that would enable a large and responsible level of OWE to be harvested. The technical areas to be integrated together in this frame will include but are not limited to metocean characterization (wind, waves, currents), composite materials, aerodynamic modeling, geo-engineering parameters, stability, fatigue, corrosion, inspection, control, renewable energy integration, social acceptance of OWE development, and impact on marine and coastal ecosystems.