Selected Grantee Publications
- 644 results found
Functional Analysis of Pathogenic Variants in LAMB1-Related Leukoencephalopathy Reveals Genotype–Phenotype Correlations and Suggests Its Role in Glial Cells
Yasuda et al., Human Molecular Genetics. 2025.
https://pubmed.ncbi.nlm.nih.gov/40237576
Cells are surrounded by a matrix, known as the basement membrane, that provides structural support and enhances signaling. Laminin B1 (LAMB1) is a matrix protein in the basement membrane that helps form this supportive structure around cells. Mutations (mistakes in the DNA sequence) in the LAMB1 gene can cause rare neurological disorders. Researchers studied the fruit fly version of the LAMB1 gene, which is LanB1. Using fruit flies, the researchers were able to gain insight into the link between LAMB1 gene mutations and disease symptoms. The LanB1 protein is found in a subset of brain cells, called glia cells, and in the blood–brain barrier. Reducing the amount of LanB1 protein in the blood–brain barrier caused shorter lifespans and movement defects in the fruit flies. Human LAMB1 was not functional in flies, but fly experiments showed that some LanB1 mutations cause severe defects, while others were milder. Tests in human cells suggested some LAMB1 mutations might cause disorders, even in the presence of a normal copy of LAMB1. This study reveals the role of LanB1 in keeping the healthy structure of the fly blood–brain barrier and understanding the consequences of different LAMB1 mutations in humans. Supported by ORIP (R24OD022005, R24OD031447).
Distinguishing PEX2 and PEX16 Gene Variant Severity for Mild, Severe and Atypical Peroxisome Biogenesis Disorders
Gomez et al., Disease Models and Mechanisms. 2025.
https://pubmed.ncbi.nlm.nih.gov/40621817
Peroxisomes are structures in cells that play an important role in metabolism and chemical changes of complex fats. Peroxisomal biogenesis disorders (PBDs) are caused by mutations in peroxin (PEX) genes. PBDs are autosomal recessive diseases—a mutated PEX gene must be passed down from both parents. In patients, symptoms of PBD range from mild to severe multi-organ system defects depending on gene mutations and even different mutations in the same gene. Researchers wanted to understand how different mutations cause the variation in symptoms seen in patients. In fruit flies, the researchers replaced the fly Pex genes with two human PEX genes—PEX2 and PEX16—and different mutant forms of these genes. Researchers found that some mutations caused severe symptoms, such as seizure-like behavior, while others were milder. Introducing a normal functional copy of the human PEX genes into the flies with mutant Pex genes alleviated the symptoms. Further studies with fruit flies will help us understand how different PEX gene mutations affect PBD severity in patients. Supported by ORIP (R24OD031447), NICHD, and NINDS.
miR-33 Inhibition as a Novel Therapeutic Approach for Treating Muscular Dystrophy
Lopez and Alexander, EMBO Molecular Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/40695995
Duchenne muscular dystrophy (DMD) is a devastating disorder caused by changes in the dystrophin gene sequence, which results in the absence of a functional dystrophin protein. Several microRNAs (a type of RNA that can bind to other molecules) can alter DMD disease by changing gene expression. In this review article, the authors discuss inhibiting microRNAs as a new therapy for DMD. Researchers have shown in a DMD mouse model that blocking miR-33a/b, a microRNA, can improve muscle regeneration (regrowth of damaged tissue) and reduce DMD symptoms. Anti-microRNA oligonucleotides (AMOs) are short chains of DNA or RNA that block microRNAs. Injection of an AMO that blocks miR-33a/b in the DMD mouse model improved muscle regrowth and increased gene pathways involved in muscle regrowth. These studies highlight the impact of microRNA signaling pathways in DMD and show how they could serve as targets for new therapies to treat the disease. Supported by ORIP (U54OD030167) and NINDS.
Genomics and Histopathology in Interstitial Cystitis/Bladder Pain Syndrome
Ruetten et al., Neurourology and Urodynamics. 2025.
https://pubmed.ncbi.nlm.nih.gov/40671333
In April 2025, researchers held a meeting to come to a global agreement on the diagnostic criteria, visible features, and possible causes of interstitial cystitis/bladder pain syndrome (IC/BPS) and to review treatment outcomes. A patient can be diagnosed with IC/BPS when they experience pelvic and bladder pain with other urinary tract symptoms, such as urinary frequency and urgency. This subreport defines the distinct differences between Hunner lesion disease (HLD) and non-Hunner lesion disease (non-HLD) in IC/BPS. HLD is an inflammatory disease of the bladder, and non-HLD is a widespread nervous system disorder in which symptoms are not limited to the bladder. This concept of distinct differences between HLD and non-HLD could be useful in identifying physical characteristics of and diagnosing IC/BPS and developing biomarkers (molecules that show a disease is present) for the condition. Supported by ORIP (T32OD010957) and NIDDK.
Mast Cells and Interstitial Cystitis/Bladder Pain Syndrome Revisited
Ruetten et al., International Urogynecology Journal. 2025.
https://pubmed.ncbi.nlm.nih.gov/40682698
A patient can be diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) when they experience pelvic and bladder pain with other urinary tract symptoms. In the United States, an estimated 3 million to 8 million women are experiencing IC/BPS symptoms. The importance of mast cells (an immune cell) in the development and progression of IC/BPS remains uncertain. A major reason for this uncertainty is significant variation in IC/BPS biopsy testing and reporting. The researchers examined 461 diagnostic pathology reports that were already completed for IC/BPS patients. Results showed that standards for histological analysis (staining the tissue and reviewing it under a microscope) of the bladder biopsies were not present. This creates inconsistent data and biopsy results, which leads to confusion about the importance of findings from pathology reports. Supported by ORIP (T32OD010957) and NIDDK.
Loss of Hepatocyte-Specific RECK Exacerbates Metabolic Dysfunction-Associated Steatohepatitis
Dashek et al., American Journal of Physiology-Endocrinology and Metabolism. 2025.
https://pubmed.ncbi.nlm.nih.gov/40758574
Metabolic dysfunction–associated steatohepatitis (MASH) is a serious liver disease resulting from excess fat buildup. MASH is a major health crisis worldwide due to increases in obesity and insulin resistance, and it is a leading cause of liver transplants in the Western world. The current approach for MASH treatment involves lifestyle changes. Therefore, identifying new ways to treat MASH is critical. Reversion Inducing Cysteine Rich Protein with Kazal Motifs (RECK) is a molecule that regulates the extracellular matrix (ECM). The ECM surrounds a cell and provides structural support and enhances signaling. The role of RECK in metabolic liver disease is poorly understood. The researchers showed in a previous study that RECK gain-of-function (increased amounts above normal) in liver cells protected mice against diet-induced MASH. In this study, researchers used two mouse models (sex not specified) that depleted RECK in liver cells. They showed that the lack of RECK significantly increased inflammation, cell swelling, and fibrosis (too much ECM). These studies highlight RECK’s potential as a novel therapy for MASH. Supported by ORIP (T32OD011126) and NIDDK.
Modeling Virus-Associated Central Nervous System Disease in Non-Human Primates
Vail et al., International Journal of Molecular Sciences. 2025.
https://pubmed.ncbi.nlm.nih.gov/40725130
Studying central nervous system (CNS) diseases that are induced by viral infection poses a unique set of challenges. First, antemortem (before death) tissue samples are not readily available for study, so CNS human disease studies must rely on end-stage postmortem (after death) assessments. Second, in vitro (outside the body) models fail to fully capture the details of an intact immune system, requiring the use of animal models to fully characterize disease development and identify potential therapies. Nonhuman primates (NHPs) are ideal models because they overcome many of the limitations posed by species that are more distant from humans, and they closely mirror human disease development and viral susceptibility. This review focuses on viruses that are known to infect the CNS—including West Nile virus, Zika virus, equine encephalitis viruses, and herpesviruses. The viruses discussed in this review article cause such CNS diseases as encephalitis (inflammation of the brain), meningitis (inflammation of the protective membrane around the brain), and myelitis (inflammation of the spinal cord), and the NHP models for viral infection are directly translatable to the human condition. Supported by ORIP (K01OD036106, P51OD011104).
Epidemiologically Relevant Phthalate Mixture and Mono (2-Ethyl-5-Hydroxyhexyl) Phthalate Exposure Alter Cell Energy Metabolism in Primary Mouse Granulosa Cells
Laws et al., Reproductive Toxicology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40324639
Many products—including plastic food containers, medical tubing, children’s toys, and personal care products—contain phthalate diesters. Phthalates leach from plastics and negatively affect the environment and female reproductive system. In women, phthalate exposure is linked to endometriosis, polycystic ovarian syndrome, and reduced fertility. The molecular pathways by which phthalate exposure affects ovaries remain understudied. Researchers tested the effects of different phthalate exposures on granulosa cells (cells that support egg cell development). Using mouse granulosa cells, the researchers found that short-term exposure to phthalates altered the expression of specific genes, Ldha and Glut1, and affected the ability to create energy. These data indicate that phthalate exposure alters metabolism in granulosa cells. Supported by ORIP (T35OD011145) and NIEHS.
Multiplexed Proteomic Biosensor Platform for Label-Free Real-Time Simultaneous Kinetic Screening of Thousands of Protein Interactions
Agu et al., Communications Biology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40119113
Existing methods for producing functional protein libraries are costly and time-consuming, and they lack real-time kinetic (protein interaction) screening abilities. Researchers developed an automated platform for high-throughput production and screening of a library of proteins on biosensor surfaces. Biosensors are devices that can bind a specific protein in a sample containing many proteins to generate a measurable signal unique to the protein of interest. This allows researchers to complete large-scale kinetic measurements for drug discovery, biomarker identification, and diagnostic development. The platform created by the researchers is known as the Sensor-Integrated Proteome On Chip (SPOC). SPOC uses nanowells to capture 2,400 proteins at the same time on a single gold biosensor chip. The SPOC biosensor chip can then be analyzed with different techniques to generate kinetic data. The SPOC will allow researchers to understand protein interactions on a large scale for research and clinical applications. Supported by ORIP (R43OD024970) and NCATS.
Determinants of Successful AAV-Vectored Delivery of HIV-1 bNAbs in Early Life
Ardeshir et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/40739359
More than 100,000 children are infected with HIV each year through vertical (mother-to-child) transmission. Antiretroviral treatment lapses can occur during postpartum care, which increases the amount of HIV virus in the mother, resulting in an increased risk of transmission to the baby through breastfeeding. Broadly neutralizing antibodies (bNAbs) defend the host from pathogens and have shown potential as a safe therapy for infants. Gene transfer using adeno-associated virus (AAV) offers an opportunity to provide preventive care for infants at risk of getting HIV. Researchers used an infant rhesus macaque model (both sexes used) for simian immunodeficiency virus (SIV)—equivalent to HIV but in nonhuman primates—to determine whether a single intramuscular injection of AAV-bNAb could protect against SIV vertical transmission. The therapy was effective at preventing SIV infection in rhesus macaque infants compared with control, nonprotected infants. Results showed that functional antibodies were present even after 4 years. This study highlights the advantages of a preclinical model because in vitro (outside the body) models cannot last in culture for years or mimic an intact immune system. These findings emphasize that a one-time intramuscular injection could provide protection for many years and supports the possible use of AAV-bNAb to protect infants from contracting HIV. Supported by ORIP (P51OD011107, P51OD011104), NIAID, NCI, and NICHD.