Selected Grantee Publications
- 644 results found
Monitoring Biological Effects of Somatic Cell Genome Editing
Freedman et al., Nature Reviews Genetics. 2026.
https://pubmed.ncbi.nlm.nih.gov/41530266
CRISPR-based genome editing is an innovative technique for treating a variety of diseases. This therapy is entering the clinic, and preclinical-to-clinical tools are needed to ensure the therapy is safe and effective. Researchers affiliated with the Somatic Cell Genome Editing (SCGE) Consortium provided a review of these efforts. The review outlines key technologies—including microphysiological systems and noninvasive in vivo (within an organism) imaging—to examine the on-target and off-target biological effects of genome editing in different organ systems and disease settings. Microphysiological systems, such as organoids and organ-on-a-chip, are useful for modeling physical characteristics of human physiology and disease. Examples of these models for a broad range of diseases and their use for gene editing applications were discussed. Challenges related to these methods were noted. The review also explained how microphysiological systems complement traditional preclinical models—including mouse models—because of species differences when compared with humans. The researchers highlighted lessons learned from the NIH-funded SCGE Biological Effects Initiative and outlined a proposed framework for the integration of these technologies into the development of genome-editing therapies. Supported by ORIP (P51OD011107, S10OD016261, S10OD018102, S10OD028713, and U42OD027094), NCATS, NHGRI, NHLBI, NIA, NIAID, NIBIB, NIDDK, NIEHS, NIGMS, and NINDS.
Therapeutic Remodeling of the Ceramide Backbone Prevents Kidney Injury
Nicholson et al., Cell Metabolism. 2026.
https://pubmed.ncbi.nlm.nih.gov/41232539
Acute kidney injury (AKI) can be caused by a broad range of conditions, including drug toxicity, sepsis, preexisting kidney disorders, and heart failure. AKI increases a person’s chance for chronic kidney disease, morbidity, and mortality, but an effective therapy for AKI is not currently available. Proximal tubules (PTs) within the kidney secrete nonfiltered substances while reabsorbing filtered molecules. Abnormal lipid metabolism and lipid imbalances are linked to AKI, but the underlying mechanisms remain unknown. Using previously published data, urine samples from patients, and 8- to 11-week-old male mouse models, researchers showed that AKI triggers the production of toxic ceramides in PTs and that urine ceramide levels correlate with disease severity. Ceramides disrupt mitochondrial structure and function by altering critical protein complexes, and damage requires a specific molecular feature of ceramides created by the DES1 enzyme. Genetic deletion of DES1 protected mice from kidney injury following bilateral ischemia reperfusion. A novel DES1 inhibitor provided a protective effect, offering a promising therapeutic strategy. This work reveals ceramide remodeling as a promising target for treating AKI. Supported by ORIP (S10OD016232, S10OD018210, and S10OD021505), NCI, NHLBI, NIA, NIDDK, and NIGMS.
A Method for Discovery of Transcription Factors Controlling Brucella sRNAs
Caudill et al., Microbiology Spectrum. 2026.
https://pubmed.ncbi.nlm.nih.gov/41230967
Regulatory small RNAs (sRNAs) control translation of many proteins that are linked to virulence (ability of the bacteria to cause disease) in pathogenic bacteria—including Brucella species—which allows for them to regulate internal processes to conserve and respond to environmental changes. For Brucella species, 40 sRNAs have been identified, but the transcription factors and conditions that control sRNAs remain unknown. In this study, researchers developed a method, by using publicly available datasets of Brucella species, to discover the transcription factors and conditions that control sRNAs. A list of predicted regulatory relationships was created, and the researchers validated several predicted regulatory relationships using Northern blots. A female mouse model also was used to identify transcription factors that may be involved in host infection by B. abortus. This method can be applied to other bacteria studies to help understand pathogenesis and the virulence factors mediated by sRNAs. Supported by ORIP (T32OD028239) and NIAID.
Gastrointestinal MAIT Cells in Chronic HIV-1 Infection
Ferre et al., Journal of Immunology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41024436
Mucosa-associated invariant T (MAIT) cells are innate-like T cells abundant in blood and the gastrointestinal tract. They help control infections by producing immunoproteins, killing infected cells, and hindering microbial growth. Chronic HIV infection reduces MAIT cells and increases vulnerability to secondary infections. In this work, researchers studied immunological responses of blood and mucosal MAIT cells to microbes between people (both sexes) with chronic HIV who are on long-term antiretroviral therapy and people without HIV. While MAIT cells were depleted in the blood of HIV-infected individuals, mucosal MAIT cell levels remained comparable between the two groups. Blood MAIT cells responded robustly to general immune stimulation. However, mucosal MAIT cells responded poorly to Escherichia coli bacterial stimulation, suggesting selective unresponsiveness to normal microbes while maintaining immune functions to other stimuli. HIV-infected individuals showed an impaired MAIT cell antimicrobial defense, providing novel insights worth studying. Supported by ORIP (S10OD018223), NCI, and NIDDK.
Targeting FSP1 Triggers Ferroptosis in Lung Cancer
Wu et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41193800
Growing evidence shows that cancer cells are highly sensitive to lipid peroxidation (a chemical process that degrades lipids in cell membranes). Ferroptosis is a form of cell death that relies on iron and lipid peroxidation, and two proteins known to suppress ferroptosis are GPX4 and FSP1. In this study, researchers used 8- to 12-week-old genetically engineered mouse models for lung cancer (both sexes used) and selectively deleted these two proteins. Results showed that deleting GPX4 and FSP1 triggered lipid peroxidation and significantly inhibited lung adenocarcinoma tumor development. FSP1 was essential for protecting tumors from ferroptosis in vivo (within an organism) but not in vitro (outside of an organism), highlighting the utility of the mouse models to mimic the physiological conditions of patients. FSP1 expression correlated with disease progression and reduced survival in lung adenocarcinoma patients (sex not stated), unlike GPX4. Drug inhibition of FSP1 showed substantial therapeutic efficacy in preclinical models. These findings establish ferroptosis as a barrier to tumor development and identify FSP1 inhibition as a promising novel therapy for lung cancer patients. Supported by ORIP (S10OD021747, S10OD032292), NCI, and NIGMS.
NSD2 Targeting Reverses Plasticity and Drug Resistance in Prostate Cancer
Li et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41299174
Most prostate cancer tumors develop resistance to therapies. In castration-resistant prostate cancer (CRPC), lineage plasticity—a cancer cell’s ability to change physical characteristics and behavior—drives disease progression and promotes drug resistance. NSD2 is a protein involved in modifying histones to change gene expression. NSD2 upregulation in neuroendocrine prostate cancer correlates with poor survival and regulates the genes that drive neuroendocrine differentiation. Using both mouse and human patient–derived organoids and 3- to 5-month-old NPp53 mice (sex not stated), researchers successfully reversed treatment resistance in neuroendocrine CRPC by inhibiting NSD2. Notably, combining NSD2 inhibition with enzalutamide (a current drug used to treat prostate cancer) effectively suppressed tumor growth and promoted cell death in multiple CRPC subtypes. These findings establish combination therapy as a promising therapeutic strategy for lethal forms of CRPC that are currently treatment resistant. Supported by ORIP (S10OD021764, S10OD012351), NCI, NIDCR, NIDDK, and NIGMS.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages
Reddy et al., Molecular Carcinogenesis. 2026.
https://pubmed.ncbi.nlm.nih.gov/41498201
Macrophages are a type of immune cell that are highly plastic—meaning environmental cues change their phenotype (physical characteristics) and behavior. Cancer cells take advantage of this plasticity to recruit and create tumor-associated macrophages (TAMs) that benefit the tumor microenvironment and promote tumor development. However, the underlying mechanism that cancer cells use to recruit TAMs remains unknown. In this study, researchers used murine and human non-small cell lung cancer cell models to show that integrin αvβ3 expression is needed to drive TAM accumulation. This research highlights a novel mechanism—αvβ3-mediated glutamine secretion—to promote TAM accumulation and begin tumor development. Developing therapies that target this signaling axis could help treat αvβ3-expressing cancers. Supported by ORIP (K01OD030513) and NINDS.
Inducing Ferroptosis to Impede Metastasis by Inhibiting the Calcium Channel TRPC6
Dimitrov et al., Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/41206865
Aggressive cancers such as triple negative breast cancer (TNBC) are able to resist standard chemotherapy and metastasize (spread to other parts of the body) quickly. Previous research shows that the calcium channel TRPC6 helps a subset of cancer cells remain quiescent (a reversable, inactive cell state), which promotes chemotherapy and ferroptosis resistance. Researchers noted that circulating tumor cells isolated from breast cancer patients displayed a higher level of TRPC6 than the primary tumor. Using in vitro (outside of an organism) experiments and 6- and 12-week-old female mice, researchers studied whether the quiescent subset of TNBC cells was sensitive to ferroptosis when targeting TRPC6. Results showed that TRPC6 can cause ferroptosis resistance. The underlying mechanism for ferroptosis resistance was that TRPC6 limits c-Myc to sustain high levels of glutathione. TNBC metastasis was significantly reduced when a TRPC6 inhibitor was used. This study supports a possible opportunity to mitigate TNBC metastasis by targeting TRPC6. Supported by ORIP (K01OD034451) and NCI.
Apparent Expansion of Virulent Vibrio Parahaemolyticus in Humans and Sea Otters
Sebastian et al., Virulence. 2025.
https://pubmed.ncbi.nlm.nih.gov/41399136
Vibriosis, caused by Vibrio species, causes about 80,000 human cases of illness in the United States each year. It is considered the most important public health threat from seafood consumption and marine recreational activities. In addition, pathogenic (disease-causing) Vibrio species infect marine animals, including otters. Although sea otters could be used as a marine bioindicator, virulence (ability of the bacteria to cause disease) factor data on Vibrio species that infect northern and southern sea otters are limited. Researchers used genomic epidemiology data to identify virulence factors of Vibrio species collected from different sources in the United States. Virulence factor prevalence varied depending on whether the isolate was environmental or derived from an organism. Specific virulence factors in V. parahaemolyticus were most prevalent in humans and northern sea otters. Co-occurrence of T3SS2 and T6SS1, two virulence factors, was linked to disease findings. This study highlights that V. parahaemolyticus undergoes selection pressures that result in the expansion of virulent strains that infect humans and sea otters. Supported by ORIP (T32OD011147).
A Porcine Model of Fanconi Anemia
Hergert et al., PLoS One. 2025.
https://pubmed.ncbi.nlm.nih.gov/41171815
Fanconi anemia (FA) is an autosomal recessive disorder (a mutated gene must be passed down from both parents for symptoms to develop). It causes birth and developmental defects because of disrupted DNA repair. Without the ability to repair DNA damage, mutations continue to collect in the patient’s tissues, which leads to anemia, bone marrow failure, and cancer. Murine (mouse and rat) models for FA do not mimic the key clinical symptoms of FA, such as anemia. A pig model of FA could accurately mimic many of the clinical features seen in human patients because pigs have similar physiology and a relatively long lifespan. Researchers targeted the FANCA gene in domestic pigs. The FANCA porcine model (sex not stated) showed skeletal abnormalities, extreme sensitivity to agents that cause DNA crosslinks (a type of DNA damage), hematopoietic progenitor cell reduction, enlarged red blood cells, and reduced neutrophil (a type of immune cell) numbers in peripheral blood. Mitomycin C treatment resulted in a tenfold increase in chromosomal radials—where a segment of one chromosome breaks off and attaches to another, causing unbalanced rearrangements due to improper DNA repair—which is a diagnostic marker for FA in patients. This study shows that the FANCA porcine model is a promising preclinical model for developing strategies to prevent bone marrow failure and malignancies in FA patients. Supported by ORIP (U42OD011140) and NHLBI.