Selected Grantee Publications
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Failure of Colonization Following Gut Microbiota Transfer Exacerbates DSS-Induced Colitis
Gustafson et al., Gut Microbes. 2025.
https://pubmed.ncbi.nlm.nih.gov/39812347/
Microorganisms that inhabit the gastrointestinal tract, known as the gut microbiome (GM), play a vital role in health and disease. Dysbiosis, the reduced richness of symbiotic commensals in the GM, exacerbates inflammation and increases inflammatory bowel disease (IBD) severity. Researchers used a mouse model for IBD to determine the role of GM composition, richness, and transfer methods on IBD disease severity. A comparison of GM transfer methods demonstrated that co-housing was not as efficient as embryonic transfer and cross-fostering. The GM of the donor and recipient during co-housing determined transfer efficiency. Transfer of a low richness GM to a recipient with high GM richness, followed by dextran sodium sulfate administration to induce IBD, resulted in significant weight loss, greater lesion severity, increased inflammatory response, and higher mortality rates. This study provides evidence regarding the role of GM composition and colonization in IBD modulation. Supported by ORIP (T32OD011126, U42OD010918) and NIGMS.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma
Ishida et al., Cancer Research Communications. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11444119
Lipids are crucial for tumor cell proliferation, and sterol regulatory element-binding protein (SREBP) activation drives lipid synthesis and uptake to maintain cancer growth. This study investigated the role of the SREBP pathway and its regulator, SREBP cleavage–activating protein (SCAP), in lipid metabolism during the development and progression of pancreatic ductal adenocarcinoma (PDAC). Using female mouse xenograft models and male and female pancreas-specific Scap knockout transgenic mice, researchers demonstrated that SCAP is essential for PDAC progression in low-nutrient conditions, linking lipid metabolism to tumor growth. These findings highlight SREBP as a key therapeutic target for PDAC, offering potential strategies for improving treatment by disrupting cancer-associated metabolic reprogramming. Supported by ORIP (T32OD011089), NCI, NHLBI, and NIGMS.
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Functional and Structural Basis of Human Parainfluenza Virus Type 3 Neutralization With Human Monoclonal Antibodies
Suryadevara et al., Nature Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38858594
Human parainfluenza virus type 3 (hPIV3) can cause severe disease in older people and infants, and the haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Researchers isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. They also delineated the structural basis of neutralization for HN and F monoclonal antibodies (mAbs). Rats were protected against infection and disease in vivo by mAbs that neutralized hPIV3 in vitro. This work establishes correlates of protection for hPIV3 and highlights the potential clinical utility of mAbs. Supported by ORIP (K01OD036063), NIAID, and NIGMS.
Time of Sample Collection Is Critical for the Replicability of Microbiome Analyses
Allaband et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38951660/
Lack of replicability remains a challenge in microbiome studies. As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design will be critical. Researchers conducted a retrospective analysis of 16S amplicon sequencing studies in male mice. They report that sample collection time affects the conclusions drawn from microbiome studies. The lack of consistency in the time of sample collection could help explain poor cross-study replicability in microbiome research. The effect of diurnal rhythms on the outcomes and study designs of other fields is unknown but is likely significant. Supported by ORIP (T32OD017863), NCATS, NCI, NHLBI, NIAAA, NIAID, NIBIB, NIDDK, and NIGMS.
Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41
Schiffner et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38816615
Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Nam, Cancer Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38588407/
Tumor-initiating cells can survive in harsh environments via stress tolerance and metabolic flexibility; studies on this topic can yield new targets for cancer therapy. Using cultured cells and live human surgical biopsies of non-small cell lung cancer, researchers demonstrated that nutrient stress drives a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. This cascade results from upregulation of integrin αvβ3, a cancer stem cell marker. In mice, pharmacological or genetic targeting prevented lung cancer cells from evading the effects of nutrient stress, thus blocking tumor initiation. This work suggests that this molecular pathway leads to cancer stem cell reprogramming and could be linked to metabolic flexibility and tumor initiation. Supported by ORIP (K01OD030513), NCI, NIGMS, and NINDS.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.