Selected Grantee Publications
- 608 results found
Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity
Ling et al., Pharmaceuticals (Basel). 2025.
https://pubmed.ncbi.nlm.nih.gov/40430490
Millions of cancer patients and cancer survivors face an increased risk of developing cardiotoxicity and cardiovascular (system encompassing the heart and blood vessels) dysfunction because of cancer progression and cancer treatments. Irregular autophagy causes this increased risk. Autophagy is the breakdown of old, damaged, or abnormal proteins within the cell that are then recycled for use in other proteins. Managing autophagy could protect the cardiovascular system during cancer treatment. This review notes the advances in regulating autophagy and how it could be applied to treat cardiotoxicity while improving cancer treatment outcomes. The researchers highlight in vitro (outside a living organism) models and other tests to discover solutions that can allow autophagy therapies to be translated into the clinic. Supported by ORIP (K01OD028205) and NHLBI.
Microbiome and Metabolome Association Network Analysis Identifies Clostridium_sensu_stricto_1 as a Stronger Keystone Genus Candidate Than Bifidobacterium in the Gut of Common Marmosets
Hernandez et al., mSystems. 2025.
https://pubmed.ncbi.nlm.nih.gov/40622159
The common marmoset is a nonhuman primate model for microbiome (the collection of microorganisms found in the body) studies. Previous studies have shown significant variation in the gut microbiome among individual common marmosets due to such factors as diet, age, sex, and captivity. Researchers identified how the gut microbiome and metabolome (the collection of molecules made or used during the chemical processes of a cell) change over time using fecal samples collected from 1- to 9-year-old healthy, captive marmosets of both sexes. Results showed that certain bacteria have a stronger influence within the gut than others. Bifidobacterium was the most abundant genus (a higher level of classification than species) of bacteria and the driver of microbiome differences among individual marmosets. Also, the results suggest that Bacteroidales bacteria compete with Bifidobacterium for resources within the gut. The researchers created a Keystone Candidate Score to identify the most influential bacteria, which were Clostridium_sensu_stricto_1 and Alloprevotella. This study provides insight into how the microbiome—including interactions among different bacteria and competition for resources—affects the health of common marmosets in captivity. Supported by ORIP (K01OD030514) and NIGMS.
Sequencing Analysis Demonstrates That a Complex Genetic Architecture Contributes to Risk for Spina Bifida
Strain et al., Birth Defects Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/41013918
Neural tube defects (NTDs) are defects of the brain, spinal cord, or spine. NTDs are the second most common type of congenital birth defect worldwide. Nucleotides are building blocks that are combined in a sequence to make DNA or RNA. Although prior studies have identified rare, harmful single nucleotide variants (SNVs) in spina bifida, broader contributions to risk remain unclear. Researchers analyzed genetic risk among 256 probands (individuals affected by the genetic disorder) compared with 395 ancestry-matched healthy controls (sex not specified). Results from their analyses identified 16 genes associated with spina bifida. Four genes were enriched in the parents, which supports the idea of inherited risk for spina bifida. This study provides insight into the many SNVs that can cause spina bifida and highlights the complex origin of the genetic disorder. Supported by ORIP (U54OD030187), NICHD, NIGMS, and NINDS.
A Potential Role for c-MYC in the Regulation of Meibocyte Cell Stress
Boyack et al., Cells. 2025.
https://pubmed.ncbi.nlm.nih.gov/40422212
The integrated stress response (ISR) controls cell survival and promotes apoptosis (a type of cell death) through the protein CHOP during prolonged or severe stress. ISR’s role in starting and advancing cancers in epithelial cells (cells that line organs and the skin) has been investigated. However, the ISR has not been evaluated in cancers originating in the glands of the eyelid, such as ocular adnexal sebaceous carcinoma (SebCA). Although SebCA is uncommon, mortality rates of up to 40% have been reported, and the mechanisms underlying SebCA tumorigenesis—the process of healthy cells transforming into cancer cells—remain unknown. Researchers studied the role of MYC in regulating the ISR in human meibomian gland epithelial cells (HMGECs) located in the eyelid. Results showed that inhibiting MYC in HMGECs stimulates the ISR, results in a smaller increase in the number of cells, and promotes apoptosis. Overexpression of MYC reduced the amount of CHOP. These data support the role of high MYC as an underlying mechanism for SebCA tumorigenesis. Supported by ORIP (K01OD034451, T35OD033655).
IMPC Impact on Preclinical Mouse Models
Hölter et al., Mammalian Genome. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12129675
The International Mouse Phenotyping Consortium (IMPC) is a global initiative to create a comprehensive collection of knockout mouse models. IMPC creates models with targeted disruptions in every protein-coding gene that shares a similar function to a human gene. These models have undergone a standardized series of analyses across multiple organ systems, which has helped researchers identify changes in key biological processes, functional pleiotropy (a single gene variation affecting multiple phenotypic traits), and sexual dimorphism (differences between males and females). The IMPC’s efforts have already resulted in more than 7,000 research publications and 294,000 citations. These efforts will accelerate disease diagnoses, identify new druggable targets, create novel therapies, and lead to effective disease prevention strategies. Supported by ORIP (UM1OD023221).
C-terminal Frameshift Variants in GPKOW Are Associated With a Multisystemic X-Linked Disorder
Mok et al., Genetics in Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/40221893
This study identifies rare mutations in the glyceraldehyde-3-phosphate dehydrogenase (GPKOW) gene that are connected to an X-linked disorder (a disorder passed down via the X chromosome) that affects multiple systems in the body. Male patients from two different families showed developmental delays; microcephaly (a neurological condition where one’s head is significantly smaller than expected for their age and sex); and eye, brain, skin, and skeletal abnormalities. Researchers completed both patient-derived cell studies and experiments in Drosophila melanogaster (fruit flies; sex not specified) to confirm that GPKOW is important for RNA processing and brain development. Overall findings show that the mutated gene produced protein instability by a partial loss-of-function mechanism, establishing GPKOW as a disease-associated gene. Supported by ORIP (R24OD022005, R24OD031447, U54OD030165).
Caspase-11 Drives Macrophage Hyperinflammation in Models of Polg-Related Mitochondrial Disease
VanPortfliet et al., Nature Communications. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12092707
Mitochondria are the energy-producing organelles within cells. Mitochondrial diseases develop from dysfunction of this organelle. These diseases lead to chronic health impairments, which can be worsened by environmental exposures—including bacterial infections. Researchers used a 7- to 12-month-old mouse model (sex not specified) to study polymerase gamma (Polg)–related mitochondrial disease. They found that infection with the bacteria Pseudomonas aeruginosa causes macrophages (a type of immune cell) to have an increased response. The response happens through cytokine-mediated increases of caspase-11 and guanylate-binding proteins, which leads to lung inflammation. These findings will help scientists find targets to develop therapies to limit infection- and inflammation-related complications in mitochondrial diseases. Supported by ORIP (U54OD030187) and NHLBI.
Generation of Inositol Polyphosphates Through a Phospholipase C-Independent Pathway Involving Carbohydrate and Sphingolipid Metabolism in Trypanosoma cruzi
Bertolini et al., mBio. 2025.
https://pubmed.ncbi.nlm.nih.gov/40172212
Millions of people are infected with the parasite Trypanosoma cruzi. T. cruzi causes Chagas disease, an infectious disease that causes damage to cardiovascular, nervous, and digestive systems. T. cruzi relies on inositol pyrophosphates (important signaling molecules) for survival. Researchers identified an alternative phospholipase C-independent pathway for producing these molecules (e.g., glucose 6-phosphate, inositol phosphoceramide). Disrupting this pathway impaired parasites’ ability to make inositol pyrophosphates. This discovery reveals a promising drug target for treating Chagas disease. Supported by ORIP (T35OD010433) and NIAID.
Detection of Live Attenuated Measles Virus in the Respiratory Tract Following Subcutaneous Measles-Mumps-Rubella Vaccination
Watkins et al., The Journal of Infectious Diseases. 2025.
https://pubmed.ncbi.nlm.nih.gov/39504437
The live attenuated measles vaccine (LAMV) is very effective in preventing measles. LAMV produces mucosal immunity in the respiratory tract, but the mechanism remains unknown. Researchers found that LAMV could be detected in the respiratory tract of children and macaques for up to 3 weeks after receiving the measles-mumps-rubella (MMR) vaccine. Scientists isolated LAMV from macaques’ lungs (sex not specified) and found that local viral activity in the respiratory tract could potentially help stimulate mucosal immunity without viral transmission. These findings highlight the importance of mucosal immune responses and provide insights as to how the MMR vaccine could protect against measles. Supported by ORIP (T32OD011089) and NIAID.
Sphingosine–1–phosphate Signaling Mediates Shedding of Measles Virus–Infected Respiratory Epithelial Cells
Brockhurst et al., Journal of Virology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40145737
Measles virus (MeV) is an infectious respiratory virus that has a significant global impact and is a major cause of childhood mortality. In 2022, MeV infection caused more than 136,000 deaths. A single infected person can transmit MeV to nearly 20 other people. Respiratory epithelial cells (cells that line the respiratory system) are the target of MeV infection, and shedding these cells into airborne droplets causes transmission to other people. Researchers used epithelial cells isolated from the tracheas of rhesus macaques (sex not specified) to understand the mechanisms underlying how MeV-infected epithelial cells are shed. Results showed that sphingosine-1-phosphate (S1P) signaling plays a key role in cell shedding. Inhibiting S1P signaling delayed MeV-infected epithelial shedding and increased the amount of virus in the epithelial lining. These findings demonstrate the key role of host cellular responses in MeV infection. Supported by ORIP (T35OD024982, T32OD011089) and NIAID.