Selected Grantee Publications
- 680 results found
Multiscale 3D Microfluidic Platform for Intraorganoid Delivery
Quezada, Research Square. 2026.
https://pubmed.ncbi.nlm.nih.gov/41646406
Neural organoids—3D structures that mimic the human nervous system—are important models for neurodevelopmental disorders and infections. Although neural organoids are more accurate than traditional in vitro models, these 3D structures lacked constant perfusion, which restricts growth and cell survival. In this study, researchers developed a 3D microfluidic delivery platform to embed flexible, thread-like microchannels into growing neural organoids. Results showed that these microchannels allow location- and time-dependent control of nutrient transport to deep-tissue microenvironments within the neural organoids. Providing growth factor–enriched fluid in the microchannels reduced programmed cell death and increased tissue integrity, which indicate enhanced survival and functional maturity of the neural organoids. These findings provide a promising strategy to probe and engineer organoid microenvironments that may lead to a more rigorous organoid model for neurological research. Supported by ORIP (S10OD032221), NCI, and NIBIB.
The GENEVA Platform Models Tumor Mosaicism to Reveal Variations of Responses to KRAS Inhibitors and Identify Improved Drug Combinations
Yu, Nature Cancer. 2026.
https://pubmed.ncbi.nlm.nih.gov/41735640
Developing a drug that is successful across a range of preclinical models is difficult because of variations of tumor responses to a therapy. In the late-stage preclinical development of drugs, xenografts (transfer of tissue from one organism to another) are the gold standard for disease models. However, xenografts require a lot of work, are expensive, and are not scalable. To overcome these limitations, researchers created GENEVA, a scalable platform that allows the study of drug responses at the single-cell level. GENEVA combines patient-derived and established cancer cell lines into 3D cultures and xenografts to capture genetic variability seen in patients within a single experiment. In tests of RAS inhibitors that target the KRAS oncogene (a gene that drives cancer) in pooled cell lines (both sexes used) and in 8- to 12-week-old xenograft female mice, results showed that mitochondrial activation promotes drug-induced cell death. The study also found that a mechanism of drug resistance is cell transition from an epithelial to mesenchymal phenotype (physical characteristics). These findings show how GENEVA improves the study of drug therapies and accelerates the translation of treatments from preclinical models to clinical use. Supported by ORIP (S10OD028511) and NCI.
Prenatal Intraportal Delivery of Polymeric Nanoparticles to Fetal Rhesus Monkeys (Macaca mulatta)
Piotrowski-Daspit, Human Gene Therapy. 2026.
https://pubmed.ncbi.nlm.nih.gov/41645533
Biodegradable and biocompatible (well-suited for living organisms) polymers—including PLGA, PACE, and PEG—are used to create nanoparticles (NPs), a type of vehicle for delivering drugs. Researchers studied fetal delivery and distribution of PLGA NPs and PACE-PEG NPs in 6- to 13-year-old female nonhuman primates (NHPs) in their second trimester. Using ultrasound, PLGA NPs and PACE-PEG NPs were injected into the fetal portal vein (major blood vessel to the liver). Results showed that after 24–48 hours, both NPs reached fetal tissues without obvious short-term harm. PLGA NPs were found in the liver and spleen, whereas PACE-PEG NPs spread to more tissue types and successfully delivered a test mRNA signal. No adverse effects were observed during the study. These early results in NHPs support the idea that NPs may one day help treat inherited genetic diseases before birth. These findings also provide evidence to support future studies in NHPs to address long-term safety and efficiency of nucleic acid therapies to treat inherited diseases. Supported by ORIP (S10OD011107, S10OD016261, S10OD018102, U42OD027094), NHLBI, NIAID, NICHD, and NIGMS.
Systems Genetic Dissection of Brain Gene Expression Reveals Excitotoxic Mechanisms of Alzheimer’s Disease
Zhao, Molecular Psychiatry. 2026.
https://pubmed.ncbi.nlm.nih.gov/41691109
Identifying the early neuropathological triggers of Alzheimer’s disease (AD) is critical to understand the mechanisms underlying cognitive symptoms observed in patients. In this study, researchers used fruit fly models to analyze the function of 30 human AD-associated gene co-expression modules (a group of genes with similar patterns). Results showed more than 340 conserved differentially expressed genes, and 141 genes were validated as genetic modifiers of neurodegeneration (nervous system damage). An amplified immune-related module was found to promote nerve cell damage, and a downregulated synaptic network contained suppressors that mitigate Aβ/tau (plaques and protein tangles) toxicity and regulate excitotoxicity (a method that causes nerve cell death). These findings establish a two-phase model in which early synaptic activation (communication between neurons) drives injury, followed by compensatory downregulation (reduced expression to counterbalance). This supports a causal link between AD pathology, gene expression, and neurodegeneration. Supported by ORIP (S10OD023469), NCI, NIA, and NICHD.
Exercise and Phellodendron amurense Extract Differentially Impinge on Oxidative Stress Response Pathways in a Mouse Model of Prostate Cancer
Patel, Scientific Reports. 2026.
https://pubmed.ncbi.nlm.nih.gov/41787055
Prostate cancer is one of the most common cancers in men. Prostate cancer progression is closely linked to oxidative stress (when unstable molecules cause damage in the cell) triggered by chronic inflammation, which disrupts protective mechanisms in the prostate. Using 8- to 10-week-old male mice, researchers studied whether exercise and Nexrutine (Phellodendron amurense tree extract) influences prostate tumor development at the transcriptomic (RNA molecules) level. Both interventions reduced the rate of high-grade tumors compared with the control. Although the underlying molecular mechanisms were different, both exercise and Nexrutine enhanced the prostate’s ability to overcome oxidative stress to protect against tumor progression. These findings support the benefits of exercise and Nexrutine as possible interventions to reduce oxidative stress and limit cancer progression. Supported by ORIP (S10OD021805), NCI, and NIA.
Enterocytes Rely on Purine Biosynthesis/Salvage Pathway to Facilitate Dietary Fat Absorption
Wang, Nature Communications. 2026.
https://pubmed.ncbi.nlm.nih.gov/41826336
Absorbing dietary fats in the intestine is an energy-demanding process. How enterocytes—cells that line the intestine and absorb nutrients—accommodate this high-energy nutrient uptake process remains unknown. In this study, researchers used a 14-week-old male mouse model, intestinal organoids, and human cell cultures. Results showed that enterocytes rely on a purine-based energy pathway and a key protein, ANKRD9, to make enough energy for packaging and exporting fats. Without ANKRD9, fat gets trapped within the enterocytes, energy levels are reduced, and total body fat is decreased in mice. These findings offer new insights into metabolism and regulation of fat absorption. Novel strategies that target ANKRD9 may be of interest to treat obesity and other metabolic diseases. Supported by ORIP (U54OD039864), NIDDK, and NIGMS.
Lifespan Pancreas Morphology for Control Versus Type 2 Diabetes Using AI on Largescale Clinical Imaging
Remedios, Clinical Anatomy. 2026.
https://pubmed.ncbi.nlm.nih.gov/41556492
Imaging the pancreas across the lifespan is critical for creating a baseline and detecting pancreatic disease, including type 2 diabetes. In this study, researchers used computed tomography (CT) and magnetic resonance imaging (MRI) to acquire a 2,533-patient dataset (both sexes used). Using artificial intelligence (AI)–driven image segmentation, pancreas size and shape across the lifespan were quantified, and a normal baseline was established. Researchers used a matched cohort of 1,350 patients—675 controls and 675 patients with type 2 diabetes—to identify consistent age- and sex-related morphological (organ structure and form) trends. CT images provided reliable measurements for AI-based assessment. Using 13 morphological features and covariate-adjusted GAMLSS statistical modeling, the study showed that 10 of the 13 morphological features studied were significantly different in type 2 diabetes compared with the controls. Type 2 diabetes patients had a smaller and differently shaped pancreas. These findings create a clinical reference of normal lifespan pancreas morphology that future AI-based detection strategies can use as a foundation to identify type 2 diabetes–related pancreatic abnormalities. Supported by ORIP (S10OD021771), NCATS, NCI, NIA, NICHD, NIDDK, and NIGMS.
Relationships Between Regional and Ectopic Adiposity and Insulin Sensitivity in Early and Late Pregnancy
Purnell, Diabetes Care. 2026.
https://pubmed.ncbi.nlm.nih.gov/41746698
Insulin resistance and obesity are risk factors for adverse outcomes during pregnancy. It remains unknown whether adiposity (fat levels) in specific tissues—including abdominal viscera (internal organs), abdominal subcutaneous (under the skin) tissue, intramyocellular (skeletal muscle) tissue, and the liver—are associated with insulin resistance during pregnancy. In this study, 59 women in early pregnancy and 47 women in late pregnancy were observed. Results showed that in early pregnancy, insulin resistance measures were strongly associated with the levels of total fat, including visceral fat and ectopic lipid in liver and muscle, highlighting the importance of fat distribution and composition. By late pregnancy, these relationships weakened when looking at glucose production and glucose disposal rates. However, liver insulin sensitivity remained associated with body mass index, abdominal fat, and intramyocellular fat. Women with pre-pregnancy obesity had greater baseline insulin resistance but fewer metabolic changes during pregnancy, highlighting the importance of pre-pregnancy fat levels. These findings emphasize that glucometabolic risk factors—insulin resistance—during pregnancy are impacted by such factors as fat location and quality rather than quantity. This study can inform targeted risk assessments and intervention strategies to reduce adverse outcomes during pregnancy. Supported by ORIP (S10OD018224, S10OD021701), NCATS, NICHD, and NIDDK.
Early-Activated Extracellular Matrix Proteins Shape the Metabolic and Spatial Dynamics of the Kidney Fibrotic Microenvironment
Gui, Nature Metabolism. 2026.
https://pubmed.ncbi.nlm.nih.gov/41776110
The extracellular matrix (ECM) surrounds cells, provides structural support, and enhances signaling. Kidney fibrosis—a condition where an excessive amount of ECM is around cells—plays a vital role in chronic kidney disease (CKD) progression. In this study, researchers determined the role of an ECM protein, ECM1, in kidney fibrosis to learn how early ECM signals shape the fibrotic microenvironment of the kidney. Results from mouse models (both sexes used), cell lines, and human serum samples (male and female patients) showed that ECM1 acts as an early regulator and links ECM remodeling to metabolic reprogramming. ECM1 signals through an integrin α2β1–RhoC–YAP axis to suppress a mitochondrial metabolic pathway necessary for creating energy via TEAD4-mediated repression of Pgc1a. Disrupting this Pgc1a axis restores function to the mitochondria, promotes tissue repair, and limits fibrotic progression as confirmed by spatial transcriptomics and proteomics analyses. These findings highlight the importance of ECM1 in driving fibrosis in CKD, so it could be a promising target for future therapies. Supported by ORIP (S10OD028483), NIDDK, and NIGMS.
Chronic Ethanol Drinking Alters Medial Prefrontal Cortex and Nucleus Accumbens Astrocyte Translatome and Extracellular Matrix Glycosaminoglycans
Hashimoto, Neuropharmacology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41713498
Alcohol use disorder causes more than 178,000 deaths each year in the United States. Previous research has shown that drinking alcohol causes alterations in neurons, but the effect of alcohol on specific brain regions and on non-neuronal cells within the brain remains poorly understood. This research examined astrocytes, which are support cells that also help regulate brain function. Using mouse models, researchers studied how chronic alcohol drinking affected astrocytes in brain regions involved in decision-making and reward. They found that alcohol changed the activity of hundreds of astrocyte-related genes, with different effects in males and females and across brain regions. The prefrontal cortex of the brain, which is involved in thinking, decision-making, and planning, was most affected in females, while a brain region involved in reward processing, the nucleus accumbens, was more affected in males. In addition, many of the affected genes were linked to communication between brain cells, energy production, immune responses, and the brain’s extracellular matrix, a supportive network surrounding cells. These findings suggest that astrocytes and other supportive components of the brain may play a key role in how chronic alcohol use alters the brain and contributes to addiction. Supported by ORIP (P51OD011092) and NIAAA.