Selected Grantee Publications
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
Assessment of Various Standard Fish Diets on Gut Microbiome of Platyfish Xiphophorus maculatus
Soria et al., Journal of Experimental Zoology Part B. 2023.
https://onlinelibrary.wiley.com/doi/10.1002/jez.b.23218
Diet is an important factor affecting experimental reproducibility and data integration across studies. Reference diets for nontraditional animal models are needed to control diet-induced variation. In a study of the dietary impacts on the gut microbiome, researchers found that switching from a custom diet to a zebrafish diet altered the Xiphophorus gut microbiome. Their findings suggest that diets developed specifically for zebrafish can affect gut microbiome composition and might not be optimal for Xiphophorus. Supported by ORIP (R24OD011120, R24OD031467, P40OD011021) and NCI.
Disentangling the Link Between Zebrafish Diet, Gut Microbiome Succession, and Mycobacterium chelonae Infection
Sieler et al., Animal Microbiome. 2023.
https://pubmed.ncbi.nlm.nih.gov/37563644/
Despite the long-established importance of zebrafish (Danio rerio) as a model organism and their increasing use in microbiome-targeted studies, relatively little is known about how husbandry practices involving diet impact the zebrafish gut microbiome. Given the microbiome's important role in mediating host physiology and the potential for diet to drive variation in microbiome composition, the authors sought to clarify how three different dietary formulations that are commonly used in zebrafish facilities impact the gut microbiome. They report that diet drives the successional development of the gut microbiome, as well as its sensitivity to exogenous exposure. Consequently, investigators should carefully consider the role of diet in their microbiome zebrafish investigations, especially when integrating results across studies that vary by diet. Supported by ORIP (R24OD010998) and NIEHS.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Photoreceptor Disc Incisures Form as an Adaptive Mechanism Ensuring the Completion of Disc Enclosure
Lewis et al., eLife. 2023.
https://elifesciences.org/articles/89160
The first steps of vision take place within a stack of tightly packed disc-shaped membranes, or discs, located in the outer segment compartment of photoreceptor cells. In rod photoreceptors, discs are enclosed inside the outer segment and contain deep indentations in their rims called incisures. This presence of incisures has been documented in several species, yet their role remains elusive. This study demonstrated that incisures are formed only after discs become completely enclosed. At the earliest stage of their formation, discs are not round but rather are highly irregular in shape and resemble expanding lamellipodia. In genetically modified mice and frogs, researchers measuring outer segment protein abundances found that incisure size is determined by the molar ratio between peripherin-2, a disc rim protein critical for the process of disc enclosure, and rhodopsin, the major structural component of disc membranes. High perpherin-2-to-rhodopsin ratio causes an increase in incisure size and structural complexity; low ratio precludes incisure formation. They propose a model whereby normal rods express a modest excess of peripherin-2 over the amount required for complete disc enclosure to ensure that this important step of disc formation is accomplished. Once the disc is enclosed, the excess peripherin-2 incorporates into the rim to form an incisure. Supported by ORIP (P40OD010997, R24OD030008).
The Drosophila Chemokine-Like Orion Bridges Phosphatidylserine and Draper in Phagocytosis of Neurons
Ji et al., PNAS. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276397/
Degenerating neurons can be cleared by phagocytosis triggered by “eat-me” signal phosphatidylserine (PS) and mediated by the engulfment receptor Draper (Drpr), yet the process is poorly understood. Investigators used several Drosophila models to study dendrite degeneration and demonstrated that the fly chemokine-like protein Orion binds to PS and mediates interactions between PS and Drpr to enable phagocytosis. This study identifies a link between immunomodulatory proteins and phagocytosis of neurons and reveals conserved mechanisms of clearing degenerating neurons. Supported by ORIP (R24OD031953, R21OD023824, S10OD018516) and NINDS.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
Early Detection of Pseudocapillaria tomentosa by qPCR in Four Lines of Zebrafish, Danio rerio (Hamilton 1882)
Schuster et al., Journal of Fish Diseases. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/jfd.13773
The intestinal nematode Pseudocapillaria tomentosa in zebrafish (Danio rerio) causes profound intestinal lesions, emaciation, and death and is a promoter of a common intestinal cancer in zebrafish. This nematode has been detected in an estimated 15% of zebrafish laboratories. Adult worms are readily detected about 3 weeks after exposure by either histology or wet mount preparations of the intestine, and larval worms are inconsistently observed in fish before this time. A quantitative PCR (qPCR) test was recently developed to detect the worm in fish and water, and here the authors determined that the test on zebrafish intestines was effective for earlier detection. Supported by ORIP (R24OD010998, P40OD011021).
Using Mass Spectrometry Imaging to Map Fluxes Quantitatively in the Tumor Ecosystem
Schwaiger-Haber et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/37208361/
Mass spectrometry imaging (MSI) can be used to identify metabolic patterns within different microenvironments of tumors but has not been fully integrated into metabolomics workflows. Investigators developed an integrated approach by combining MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to study metabolic pathways across the brains of mice harboring GL261 glioma, a mouse model for glioblastoma. This study reveals the importance of multiple anabolic pathways, including fatty acid elongation flux, in glioma. Supported by ORIP (R24OD024624).
Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Antitumor Immunity in Prostate Cancer
Wang et al., Science Translational Medicine. 2023.
Prostate cancers often escape immune detection and destruction. Investigators report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer. They found that NRP2 depletion increased T cell activation in vitro. Additionally, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody resulted in necrosis and tumor regression. These findings provide justification for the initiation of clinical trials using this function-blocking antibody in treatment of prostate cancer, especially for patients with aggressive disease. Supported by ORIP (R24OD026440) and NCI.