I employed the genetic toolkit available in the fruit fly Drosophila melanogaster as a model system to screen for small molecules that promote neuronal regeneration. Specifically, I focused on the olfactory system, in which olfactory sensory neurons (OSNs) are located in the peripheral antennae and are therefore readily accessible for labeling and imaging to assess drug efficacy.
First, using genetic and molecular approaches, I identified persistent OSN loss throughout the lifespan of Drosophila, increasing in an age-dependent manner. In parallel, genetic lineage tracing and incorporation of molecular markers revealed sustained OSN regeneration over time, suggesting continuous neuronal turnover to maintain tissue homeostasis. To further support this, I implemented an imaging and computational segmentation pipeline to quantify individual OSNs across the lifespan. OSN numbers remained stable during approximately the first 40% of the lifespan, followed by a significant age-dependent decline. These findings identify a critical window during which neuronal homeostasis becomes disrupted and may be most amenable to intervention aimed at prolonging neuronal survival.
Second, I established an in vivo drug screening platform in Drosophila. I developed a strategy for oral drug administration during the first week of adult life, followed by antennal microdissection and high-resolution imaging to quantify OSN numbers after treatment. To account for potential sex-specific effects, antennae from both male and female flies were analyzed for each condition. Using this platform, we assessed approximately 60 compounds previously reported to modulate stem cell activity in vitro or in other in vivo systems, achieving single-cell resolution. This approach identified three candidate molecules for further investigation: two increased OSN numbers in a sex-dependent manner and have been reported to promote neurogenesis in rodent models, while a third significantly reduced OSN numbers, consistent with findings in other in vitro systems. These results validate the platform as a cost- and time-efficient in vivo screening approach for identifying biologically relevant compounds. In the next phase, the screen will be expanded, and candidate molecules will be tested in ageing and neurodegenerative contexts to evaluate their ability to preserve neuronal homeostasis.
Third, I received training in the culture and expansion of human induced pluripotent stem cells (hiPSCs) and their differentiation into neural stem/progenitor cells. This platform will be used to evaluate the identified compounds for their ability to promote neurogenesis in a human-relevant system, thereby strengthening the translational potential of the approach.
Finally, I undertook training in a non-academic setting to gain first-hand experience in innovation and the translation of research findings. For this, I joined the biotech startup brainQr Therapeutics GmbH, where I contributed to the development of compounds promoting neuronal survival in neurodegenerative conditions. In particular, I supported Investigational New Drug (IND)-enabling studies aimed at advancing two proprietary candidates from animal models toward first-in-human testing. This experience provided specialized skills not typically accessible in academia, particularly in innovation and research translation, and positions me to apply similar strategies to the future development and exploitation of candidate molecules identified in my own work.
