Gas-rich galaxy centers like our own Milky Way's Central Molecular Zone (CMZ) are amongst the most extreme, yet poorly understood, environments for star formation. These regions are affected by large-scale in- and out-flows of gas, by nuclear starburst and/or active galactic nuclei, which makes them unique laboratories in the local universe to study star formation at the highest gas and stellar mass densities, intense radiation fields, and short (<50 Myr) dynamical timescales. CMZs are compact (<1kpc) and subject to high extinction, which requires near- to mid-infrared observations to study their individual star-forming sites. The lack of data that resolves the molecular gas reservoirs and star formation sites has prevented establishing a coherent picture of this star formation regime – a situation that has now radically changed by JWST. At the same time, ALMA has both the sensitivity and spatial resolution to map the underlying gas distribution. This ERC project will develop a first synthetic view of extragalactic CMZs (eCMZs) by zooming in to centers of 37 nearby galaxies from a sample that has been globally well characterized through the PI's PHANGS survey. The PI has assembled in a set of observational campaigns an absolutely unique ALMA+HST+JWST dataset, with unprecedented 5-30pc resolution. Rigorous analysis of these data will provide the urgently needed observational framework to distinguish between theories for star formation under extreme CMZ conditions: it may either argue for a highly time-variable star formation dominated by local processes, or for a more steady-state evolution regulated by the larger-scale environment.

The PIRL concept is the first method of any to achieve surgery without scar tissue formation. This new laser concept has achieved the long held promise for the laser for attaining the fundamental limit to minimally invasive surgery. The very prospect of high precision surgery without scar tissue formation is readily appreciated to potentially revolutionize surgery and holds equally great promise in providing in situ bio-diagnostics. The goal of this work is to develop a more compact and higher power version of the ERC SUREPIRL (ERC AdG_20110209, project ID 291630) project’s laser system with improved beam quality and delivery methods to drive adoption of the concept and open up commercial surgical and bio-diagnostic applications. The current cross-disciplinary collaboration between the physicists, chemists, and surgeons within the SUREPIRL project has led to significant advancements in knowledge as to demands on beam power and beam shape necessary for full scale commercial implementation of this technology. This proposal builds upon the unique applications enabled by the novel PIRL technology – currently under investigation by the SUREPIRL project – to develop a new laser device based on direct amplification of 3 µm laser radiation. Recent advances in the field of research on Chromium-doped chalcogenide gain materials make it possible to realize sufficient power amplification in this wavelength region on the picosecond pulse timescale. This potential gain in power and reduction in size will permit for the rapid translation of SUREPIRL project findings to industry, with significant commercial and societal benefit.

Proteins function only after folding into complex three-dimensional shapes. Loss of protein conformation is detrimental for cellular health, and a hallmark of aging and diverse human diseases. To ensure proteome integrity, cells rely on an intricate interplay between protein synthesis, folding, and quality control. Since proteins often begin to fold during mRNA translation, codon choice and tRNA supply can promote this process by modulating translation speed. How metazoans exploit this mechanism to ensure protein homeostasis over a wide range of cells and tissues, or why some cell types are more vulnerable to translation defects and proteome damage remains unknown. Here, I will define how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialized proteomes in different cell types. I propose a multiscale systems approach centred around: i) stem cells and differentiated progeny lines as a powerful model system, and ii) a novel method to modulate cellular tRNA pools in vivo. Isogenic lines of a range of normal cellular states will be created through the differentiation of human pluripotent stem cells into neuronal and cardiac lineages. In these lineages, I will first quantitate tRNA expression and abundance, and dissect their impact on translation dynamics with ribosome profiling. Second, I will use systematic depletion of individual tRNAs to explore how different cell types respond to imbalanced tRNA pools, and define how mRNA sequence and protein structure patterns program protein folding. Third, I will use loss-of-function screens to uncover evolutionarily conserved regulators of proteome integrity as a function of cell identity. This project will define how diverse metazoan cell proteomes are established and maintained, and reveal why some cells tolerate misfolded proteins better than others.

PROteolysis TArgeting Chimera (PROTAC) is a new and attractive therapeutic approach that regulates a target protein by channeling it to the proteasome for degradation (an energy-demanding pathway). Concurrently, proteasomes also play a central role in generating the peptide repertoire for antigen presentation on the Human Leukocyte Antigen-I (HLA-I) molecules. A few years after PROTAC was invented, proteasomes were found to catalyze not only canonical peptide bond hydrolysis, but are also capable of “cut-and-paste” events, i.e. generating spliced peptides, which have been shown to be frequently presented n HLA-I immunopeptidomes. It is unclear how PROTAC-driven proteasome degradation modulates the spliced and non-spliced peptide repertoire derived from a targeted protein. Alterations in peptide variety and quantity produced by proteasome may lead to strong implications on the HLA-I immunopeptidome, and, hence, could result in immune implications. Therefore, using the key oncoprotein KRAS as a PROTAC’s target, this study intends to understand: (i) how PROTAC-driven KRAS degradation affects cellular pathways on a system-wide level; (ii) the impact of PROTAC on KRAS derived peptide repertoire generated by proteasomes; (iii) to what extent PROTAC enhances KRAS derived peptide presentation on HLA-I molecules. Through the combination of a multidisciplinary approach; molecular biology, biochemistry, proteomics, bioinformatics and cellular immunology, this study will provide a better fundamental understanding of the effect of PROTAC-KRAS on the cellular proteome, proteasome-derived peptide repertoire (spliced and non-spliced peptides) and HLA-I immunopeptidome landscape, thus, provide insights into the suitability of PROTAC-KRAS application as a therapeutic approach for anti-cancer therapies. Additionally, this project will deepen our understanding of the role of spliced peptides in the antigen processing and presentation pathway.