Acute ischemic strokes result from the occlusion of cerebral vessels by blood clots causing neurological complications, brain damage and death. Based on WHO reports, stroke affects 17M people per year worldwide, with 6M deaths and 5M survivors suffering long-lasting disabilities. Recent statistics estimate an EU direct healthcare cost for stroke of €20B and indirect costs, due to disabilities and lost productivity, of €25B. The two current treatments – thrombolysis and thrombectomy – come with limitations and considerable side effects. Thrombolysis can be safely administered only to a small cohort of patients (about 5%) whereas thrombectomy induces disabilities in 50% of the cases. Moved by the societal, economical, and emotional burden associated with stroke, this proposal aims at developing and validating more effective and less toxic therapies via the combination of the clinically approved molecule tPA and rationally-designed, discoidal polymeric nanoconstructs (DPNs). As compared to tPA, the proposed thrombolytic nano-agents (tPA-DPNs) are expected to provide faster blood clot dissolution; safer administration profile; longer blood circulation and stability. On the technical side, tPA-DPNs will be re-designed to improve their biodegradation and excretion profiles; validated in FDA-recognized stroke models for neurotoxicity and therapeutic efficacy. On the commercial side, a patent portfolio covering the fabrication and utilization of tPA-DPNs will be secured, together with thorough market and business analyses. This will facilitate the interaction with pharmaceutical companies that are investing in the fast growing markets of high-tech drug delivery systems and stroke diagnostics and therapies. tPA-DPNs are expected to alleviate the economic burden on healthcare systems, increase the total sale of thrombolytic agents, revolutionize the medical protocols for stroke management, and diminish the societal and emotional impact of stroke.
Infrared light-emitting diodes (IR-LEDs) serve a broad range of applications including fiber-optic communications, night vision as well as clinical diagnosis and biomedical imaging. Within the family of nanomaterials, colloidal semiconductor quantum dots (QDs) offer exceptional promises for IR-LEDs due to their unique optical properties and low-cost solution-processability. So far, state-of-the-art QD IR-LEDs are based on lead-containing QDs, which has been severely restricted by the environmental directives e.g. EU’s “Restriction of Hazardous Substances” (RoHS). In fact, current challenges of IR-LED technology are to identify and develop novel and efficient lead-free QDs. INFLED aims at demonstrating the first RoHS-compliant and efficient QD IR-LED based on innovative and environmentally friendly material design and device engineering. The project targets the most efficient heavy metal-free infrared QD using a novel synthesis technique as well as rationally nanoengineering at material level. Furthermore, the resultant design at device level will lead to low trap state density, high solid-state quantum efficiency and thereby efficient LEDs. Hence, the key objectives of this proposal are: i) a novel QD synthesis method; ii) material design at nanocrystalline level; iii) LED device engineering at supra-nanocrystalline level. INFLED is at the crossroad of chemistry, physics and engineering, and therefore is expected to attract significant attention from different disciplines along with offering new insights toward next-generation infrared and quantum network technology.
Aggregation of RNA binding proteins (RBPs) is a pathological hallmark of neurodegenerative pathologies such as Amyotrophic Lateral Sclerosis. The mechanism leading to RBP aggregation relies on the ability of these proteins to transition into membrane-less compartments such as the stress granules (SG) whose formation is normally regulated in physiological conditions. Yet, as RBPs are intrinsically prone to coalesce in large assemblies, their accumulation, when unregulated, can lead to cell toxicity. While the effects of amino acid mutations on RBP aggregation have been extensively investigated, a large amount of evidence indicates that nucleotide variants in untranslated regions (UTRs) can strongly impact RBP expression by altering the interactions with specific regulatory proteins. UTRs provide a platform where multiple RBPs bind to orchestrate post-transcriptional regulation. I envision that UTRs, by directing contacting specific protein networks are crucial in aggregate formation and that alteration of their interactomes—due to disease-linked mutations—could impact the propensity to form SG and other assemblies. The main objective of UNDERPIN is to reveal interactions in regulatory regions of RBPs and to understand their effects on phase separation in physiology and pathology. Firstly, I plan to investigate the effects of disease-linked mutations on UTRs of RNAs encoding RBPs by large-scale predictions of UTR-RBP interactors. Secondly, interactions between RBP and selected UTRs, with and without disease-linked mutations, will be revealed in human cells by RNA-protein interaction detection experimental method RaPID. Finally, the biological implications of UTR-mediated recruitment of RBPs will be deciphered providing molecular details on how UTRs and RBPs promote the formation of aggregates. Successful completion of this project will not only lead to new insights into RBP biology, but will also pave the way to understand early events of neurodegeneration.