Selected Grantee Publications
- 644 results found
In Utero Rescue of Neurological Dysfunction in a Mouse Model of Wiedemann-Steiner Syndrome
Reynisdottir et al., JCI Insight. 2025.
https://pubmed.ncbi.nlm.nih.gov/40956618
Wiedemann-Steiner syndrome (WDSTS) is a rare, autosomal dominant (only one mutated gene copy is needed for symptoms to develop) genetic disorder that causes intellectual disability, abnormal facial features, and reduced growth. WDSTS occurs when the histone lysine methyltransferase 2A (KMT2A) protein is mutated. In previous studies using mouse models, syndromes related to WDSTS, such as Rett and Kabuki, have shown promise in being treatable after birth. The researchers created a mouse model for WDSTS (both sexes used) and showed that the genetic disorder could be treated in the womb by restoring KMT2A protein function. This model could be used in future studies to identify possible therapies and the window for treatment. Supported by ORIP (U54OD030187).
Structural and Functional Basis of Mechanosensitive TMEM63 Channelopathies
Zheng et al., Neuron. 2025.
https://pubmed.ncbi.nlm.nih.gov/40480214
Mechanotransduction occurs when cells sense changes in outside physical forces and convert them into electrical or chemical signals. To complete this process, certain ion channels are used, such as transmembrane protein 63A (TMEM63A), to pass ions and fats across cell membranes. TMEM63B and TMEM63C are part of the same protein family as TMEM63A. Mutations in these three channels cause neurodevelopmental disorders. Researchers identified the changes in protein structure and function for common TMEM63A and TMEM63B mutations. The results provide insight into TMEM63 channel dysfunction. Supported by ORIP (R21OD037849), NIDCD, and NIGMS.
Estimating Realized Relatedness in Free-Ranging Macaques by Inferring Identity-by-Descent Segments
Freudiger et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39808663
Biological relatedness is a key consideration in studies of behavior, population structure, and trait evolution. Except for parent–offspring dyads (pairs), pedigrees (diagrams that show family member relationships) do not capture individual relatedness perfectly. The number and length of identical-by-descent (IBD) segments of DNA yield the most precise estimates of being related. The researchers used different methods to estimate IBD segments in free-ranging rhesus macaques (both sexes used). Then, they compared the IBD-based estimates to current methods, such as pedigree. The results show that IBD-based estimates are more reliable and provide more detailed information about relationships. Future population studies can use this accurate method to investigate predictors and consequences of being genetically related in natural populations. Supported by ORIP (P40OD012217, P51OD011092), NHGRI, NIA, and NIMH.
A STAT3/Integrin Axis Accelerates Pancreatic Cancer Initiation and Progression
Campos et al., Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/40701148
In pancreatic ductal adenocarcinoma (PDAC), inflammation and cell stress within the environment surrounding the tumor are known to promote cancer cell growth and increase drug resistance. The signal transducer and activator of transcription 3 (STAT3) pathway directs these responses. Researchers used human cancer cells and mouse models for PDAC (both sexes used) to identify binding sites of STAT3 that regulate gene expression and are linked to poor survival. The results showed that STAT3 interacts with integrin beta 3 to start and grow PDAC tumors. STAT3 also targets 18 genes that are involved in adaptive responses and can be used to identify different survival outcomes. This study highlights a new way to classify PDAC subpopulations for STAT3-targeted therapies. Supported by ORIP (K01OD030513), NCI, and NIGMS.
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).