Biology subjects

Pavlou, M.

Publications and source records attributed to Pavlou, M..

3 recordsLinked to original sources

bioRxiv2024

AAV-mediated expression of proneural factors stimulates neurogenesis from adult Müller glia in vivo.

The lack of regeneration in the human central nervous system (CNS) has major health implications. To address this, we previously used transgenic mouse models to show that neurogenesis can be stimulated in the adult mammalian retina by driving regeneration programs that other species activate following injury. Expression of specific proneural factors in adult Muller glia causes them to re-enter the cell cycle and give rise to new neurons following retinal injury. To bring this strategy closer to clinical application, we now show that neurogenesis can also be stimulated when delivering these transcription factors to Muller glia using adeno-associated viral (AAV) vectors. AAV-mediated neurogenesis phenocopies the neurogenesis we observed from transgenic animals, with different proneural factor combinations giving rise to distinct neuronal subtypes in vivo. Vector-borne neurons are morphologically, transcriptomically and physiologically similar to bipolar and amacrine/ganglion-like neurons. These results represent a key step forward in developing a cellular reprogramming approach to regenerative medicine in the CNS.

neuroscience↗

bioRxiv2022

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of Phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PIK3/Akt signaling which regulates the cell cycle and spliceosome machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models. Key pointsO_LIMutational loss of PIK3R1 induces resistance to NOTCH1 inhibition in T-ALL C_LIO_LIPharmacological Notch inhibition synergizes with CDK4/6 inhibitors in T-ALL C_LI

cancer biology↗

bioRxiv2019

A proteogenomic resource enabling integrated analysis of Listeria genotype-proteotype-phenotype relationships

Listeria monocytogenes is an opportunistic foodborne pathogen responsible for listeriosis, a potentially fatal foodborne disease. Many different Listeria strains and serotypes exist, but a proteogenomic resource that bridges the gap in our molecular understanding of the relationships between the Listeria genotypes and phenotypes via proteotypes is still missing. Here we devised a next-generation proteogenomics strategy that enables the community to rapidly proteotype Listeria strains and relate this information back to the genotype. Based on sequencing and de novo assembly of the two most commonly used Listeria model strains, EGD-e and ScottA, we established two comprehensive Listeria proteogenomic databases. A genome comparison established core- and strain-specific genes potentially responsible for virulence differences. Next, we established a DIA/SWATH-based proteotyping strategy, including a new and robust sample preparation workflow, that enables the reproducible, sensitive, and relative quantitative measurement of Listeria proteotypes. This reusable and publically available DIA/SWATH library covers 70% of open reading frames of Listeria and represents the most extensive spectral library for Listeria proteotype analysis to date. We used these two new resources to investigate the Listeria proteotype in states mimicking the upper gastrointestinal passage. Exposure of Listeria to bile salts at 37 {degrees}C, which simulates conditions encountered in the duodenum, showed significant proteotype perturbations including an increase of FlaA, the structural protein of flagella. Given that Listeria is known to lose its flagella above 30 {degrees}C, this was an unexpected finding. The formation of flagella, which might have implications on infectivity, was validated by parallel reaction monitoring and light and scanning electron microscopy. flaA transcript levels were not significantly different with and without exposure to bile salts at 37 {degrees}C, suggesting regulation at the post-transcriptional level. Together, these analyses provide a comprehensive proteogenomic resource and toolbox for the Listeria community enabling the analysis of Listeria genotype-proteotype-phenotype relationships.

systems biology↗