Selected Grantee Publications
- 608 results found
Metabolomic Profiling and Characterization of a Novel 3D Culture System for Studying Chondrocyte Mechanotransduction
Brahmachary et al., Cellular and Molecular Bioengineering. 2025.
https://pubmed.ncbi.nlm.nih.gov/41328310
Osteoarthritis (OA) is a chronic degenerative joint disease that affects more than 37% of people over age 60. The pericellular matrix (PCM), the microenvironment that directly surrounds each cartilage cell, plays an important role in mechanotransduction. This process allows cells to sense changes in outside physical forces and convert them into electrical signals and cartilage functions. Using a novel 3D culture system equipped with cyclical compression and loading stimulation to mimic physiological conditions, researchers studied human and bovine cartilage cell mechanotransduction under different cell culture conditions. Metabolomic profiling—a way of observing all chemical changes within a cell that produces compounds and energy for biological processes—showed unique changes and strong PCM development as indicated by the production of both collagens VI and II, suggesting the 3D culture system replicates the native PCM and physiological stiffness of cartilage. By providing a physiologically relevant 3D model, future studies can look into OA pathways, cartilage tissue engineering, and novel therapies. Supported by ORIP (S10OD028650), NIAMS, and NIGMS.
Cryo-EM Structures of HBV Capsids from Human Cells at Near-Atomic Resolution
Bianchini et al., Structure. 2025.
https://pubmed.ncbi.nlm.nih.gov/41314213
More than 800,000 deaths per year are caused by hepatitis B virus (HBV)–induced liver inflammation, cirrhosis (scarring liver), and hepatocellular carcinoma. Cryogenic electron microscopy (Cryo-EM) is a microscope technique that images samples cooled to very low temperatures. Using cryo-EM, researchers determined the structure of HBV capsids (a protein shell that surrounds and protects the virus) purified from human cells. Along with computer simulations and analyses, results highlighted the dynamic regulation of HBV capsid structure and how it contributes to virion (an infectious form of virus) secretion, viral assembly, and envelopment. This could be a potential mechanism for developing HBV-specific antiviral drugs for disease treatment. Supported by ORIP (S10OD028725), NIAID, and NIGMS.
Macrophage-Engaging IgG4 Antibody Triggers Cytotoxicity Against Integrin αvβ3+ Cancers
Reddy et al., Molecular Cancer Therapeutics. 2025.
https://pubmed.ncbi.nlm.nih.gov/41081633
Integrins are cell receptors that span the cell membrane and play an important role in signaling pathways—including survival and movement. Integrin αvβ3 is absent in most normal cells and is a biomarker of cancers that form in the epithelial tissue, lining most organs and body surfaces. Integrin αvβ3 also is a driver of tumor stemness (properties of cancer cells that promote tumor development) and drug resistance in epithelial cancers, which makes it an ideal target for therapy. Tumor-associated macrophages (TAMs) are immune cells that are abundant in the epithelial cancer microenvironment, but they reduce the efficacy of an antibody therapy that targets cells with integrin αvβ3. Using in vitro (outside of the body) cultures and 8- to 10-week-old female mice, researchers revealed an antibody-mediated therapy that activates the anti-tumor activities of TAMs to overcome drug-resistant, integrin αvβ3-positive epithelial cancer. This study supports the use of antibody-based therapies to activate immune cells and destroy the tumor. Supported by ORIP (K01OD030513), NCI, NIDDK, and NINDS.
Cross-species Protection Suggests Entamoeba histolytica Trogocytosis Enables Complement Resistance Through the Transfer of Negative Regulators of Complement Activation
Ruyechan et al., Infection and Immunity. 2025.
https://pubmed.ncbi.nlm.nih.gov/40741974
Amoebae are single-cell organisms that can be parasites to the human body. Entamoeba histolytica, a type of amoeba, causes diarrheal disease when it invades the intestine. E. histolytica spreads through the body using the bloodstream and can evade the immune system. Amoebae eat parts of human cells—an event known as trogocytosis—which allows them to display human proteins and resist being broken down by serum in the blood. Researchers wanted to identify how amoebae resist being broken down. Results showed that amoebae display host proteins that suppress the complement pathway of the immune system, which protects them from being broken down. Other microbes can perform trogocytosis of human cells, so understanding this method of resistance could be relevant to other infections. Supported by ORIP (T32OD011147) and NIAID.
Alternating Hemiplegia of Childhood Associated Mutations in Atp1a3 Reveal Diverse Neurological Alterations in Mice
Terrey et al., Neurobiology of Disease. 2025.
https://pubmed.ncbi.nlm.nih.gov/40381892
Pathogenic variants (changes in a gene that increase a person’s risk of developing a genetic disorder) in the Na+/K+ ATPase transmembrane ion transporter (ATP1A3) gene cause a spectrum of neurological disorders, including alternating hemiplegia of childhood (AHC). In patients, about 65% of AHC cases are caused by one of two specific mutations. Mouse models that mimic these mutations are limited by early death, which hinders our understanding of the molecular and cellular mechanisms that drive AHC. The researchers used a hybrid approach to create mouse models for these two most common ATP1A3 variations that did not suffer from early death. The researchers characterized the mouse models (both sexes used) and found that the two ATP1A3 variations cause different disease symptoms, including motor function impacts, behavior changes, and the inflammation of nervous system tissue. These mouse models can be used to test possible therapies for AHC. Supported by ORIP (U54OD030187, U42OD010921).
Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model
Kumar et al., Biomolecules. 2025.
https://pubmed.ncbi.nlm.nih.gov/40149917
The Mojave rattlesnake is highly venomous and is found in Southern and Southwestern states. If a person is not treated after being bitten, there is a 30% to 40% chance of death. This rattlesnake’s venom can contain Mojave toxin (MTX), which is a neurotoxin (a substance that damages the nervous system). Using neural cells created from induced pluripotent stem cells (iPSCs; cells that are able to become many different types of cells found in the body), researchers identified the molecular pathways that the venom alters in nervous system cells. The results showed that a type of protein, metalloprotease, found in the venom acts on the extracellular matrix (a substance that surrounds the cells to provide structural support and enhance signaling). MTX triggers multiple cell-signaling cascades, mitochondrial (the structure within a cell that makes energy) toxicity, and cell death. Supported by ORIP (P40OD010960), NHGRI, NHLBI, NIA, and NIGMS.
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.