Selected Grantee Publications
- 666 results found
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.
In Vivo Prime Editing Rescues Alternating Hemiplegia of Childhood in Mice
Sousa et al., Cell. 2025.
https://pubmed.ncbi.nlm.nih.gov/40695277
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disease that can cause involuntary muscle contractions, low muscle tone, paralysis on one side of the body, abnormal eye movements, seizures, and intellectual disability. There is currently no treatment. AHC is caused by a mutation in the gene ATP1A3; three variations of the ATP1A3 gene mutation are responsible for 65% of cases. Researchers used prime editing and base editing tools to correct ATP1A3 gene mutations in cells isolated from AHC patients and two mouse models for AHC (sex not specified). Results showed that physical characteristics of AHC were corrected and that treated mice had an extended lifespan. These findings support the potential use of prime editing and base editing tools to treat a neurological disease. Supported by ORIP (U54OD030187, U42OD010921), NHGRI, NIGMS, and NINDS.
Advances in Host-Directed Therapy for Tuberculosis and HIV Coinfection: Enhancing Immune Responses
Prasanna et al., Trends in Microbiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40345900
A quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb); however, 90% to 95% of people with Mtb are asymptomatic (meaning they do not show symptoms) and are considered to have LTBI (latent tuberculosis [TB] infection). People with immunosuppressive conditions, such as HIV, however, are at higher risk for symptomatic TB that can spread to other organs beyond the lungs. When people with Mtb become infected with HIV, Mtb-specific CD4+ T cells are reduced, and inflammation is increased from chronic immune cell activation. This promotes the progression of TB. Coinfected people also can suffer from drug-resistant infection, drug toxicity, or incomplete pathogen clearance, which highlights the need for additional therapies. To potentially improve clinical outcomes of HIV and TB coinfection, host-directed therapy (HDT) has emerged as a promising addition to current treatments. This review discusses several kinds of HDTs—including cytokine therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy, and immune checkpoint inhibitors. HDTs restore normal immune cell function and minimize inflammation. This review highlights the potential use of HDTs with current HIV and TB therapies to reduce the prevalence of coinfection. Supported by ORIP (K01OD031898) and NIAID.
Dia–B–Ties: B Cells in the Islet–Immune–Cell Interface in T1D
Hilliard et al., Biomolecules. 2025.
https://pubmed.ncbi.nlm.nih.gov/40149868
Roughly 30 million people worldwide suffer from type 1 diabetes (T1D). T1D is an autoimmune disease that requires lifelong use of insulin. A key feature of T1D is T cell–driven damage of insulin-producing β islet cells in the pancreas. This review discusses the role of B lymphocytes (an immune cell) in T1D disease development and progression. B lymphocytes are an essential mediator of communication between other immune cell types and islet cells in what is known as the islet–immune interface. B lymphocytes coordinate communication among different cell types through antigen (a substance that tells your immune system whether something is harmful) presentation, cytokine secretion, and antibody production. Using these methods, B lymphocytes activate autoreactive (an antibody that targets a normal molecule within a person) T cells that target islet cells, which amplifies inflammation in the pancreas during the initial stages of T1D development. The review outlines current and potential therapies that target B lymphocytes. These therapies potentially could be beneficial in T1D treatment. Supported by ORIP (K01OD028759, R03OD036470) and NIAID.
Acute Degradation of Nucleolin Reveals Its Novel Functions in Cell Cycle Progression and Cell Division in Triple Negative Breast Cancer
Mills et al., Journal of Experimental and Clinical Cancer Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/40653460
The nucleolus is a vital compartment within the cell where ribosomes (which link amino acids together to form proteins) are assembled. Traditional experimental methods cannot deplete nucleolar proteins (proteins that make up the nucleolus) while keeping the cell alive, which limits our understanding of the biological functions of these proteins. Researchers used two advanced techniques to successfully deplete and identify the biological functions of nucleolin (NCL) in triple-negative breast cancer (TNBC) cells. NCL is one of the most abundant nucleolar proteins in the body. Results showed that depleting NCL in TNBC cells causes defects in cytokinesis, a step in cell division. Defects in cell division result in a smaller increase in TNBC cell numbers. Cancer therapies that target cellular mitosis (the process of a single cell dividing into two new cells) were more useful when NCL was degraded. This research supports a new role of NCL in TNBC cell division and reveals that inhibiting NCL may enhance cancer therapies. Supported by ORIP (K01OD031811) and NCI.
The Atypical Quorum Sensing System of Classical Brucella Species
Caudill and Caswell, Journal of Bacteriology. 2025.
https://pubmed.ncbi.nlm.nih.gov/41222302
Brucella species are a major public health concern because they trigger disease in both animals and humans and cause global economic losses. These bacteria have evolved to replicate in host cells—particularly macrophages (a type of immune cell). Brucella species have a specialized quorum sensing system (a way that bacteria communicate with each other using signaling molecules) that is essential for infecting the host and intracellular trafficking (the process of moving various components within the cell). This review describes the typical aspects of Brucella quorum sensing. Areas of limited knowledge that require additional research also are discussed. Supported by ORIP (T32OD028239) and NIAID.
Dominant Effects of the Immediate Environment on the Gut Microbiome of Mice Used in Biomedical Research
Ericsson et al., mSystems. 2025.
https://pubmed.ncbi.nlm.nih.gov/41222144
One potential concern when using mouse models is their reproducibility and predictive value for human disease. However, genetically engineered mouse (GEM) models are vital for studying gene function and the effects of environmental factors in biological systems. The microbiome (the collection of microbes found in the body) of GEM models significantly influences model phenotypes (physical characteristics) and thus represents a possible source of poor reproducibility. Researchers collected fecal samples from 275 unique GEM models at 84 different research institutions. These research institutions were located across 34 U.S. states and 7 other countries. Results showed that the laboratory environment was the main factor in shaping the microbiome, and beta-diversity similarities were observed. A surprisingly high prevalence and amount of Helicobacter species was observed in the GEM model microbiomes. This highlights the importance of collecting fecal samples in phenotyping studies to understand how the microbiome affects the results. Supported by ORIP (U42OD010918).
A Tandem Repeat Atlas for the Genome of Inbred Mouse Strains: A Genetic Variation Resource
Ren et al., iScience. 2025.
https://pubmed.ncbi.nlm.nih.gov/41142115
Tandem repeats (TRs) are repetitive DNA sequences. TRs are a significant source of genetic variation in the human population, responsible for unique biomedical traits among individuals and more than 60 genetic diseases. Researchers used long-read sequencing and state-of-the-art computational programs to produce a database of more than 2 million TRs that cover 39 inbred mouse strains (males used). Results showed that there were important similarities and differences among species and that TR alleles (alternative versions of a gene) are important for genetic discovery. Analysis of two biomedical phenotypes (physical characteristics), which were characterized in inbred mouse strains more than 40 years ago, identified the genetic factors that can cause these phenotypes. This research is essential for characterizing the unique genetic variations that cause trait differences and advancing fundamental biological research and translational medicine. Supported by ORIP (R24OD035408) and NIDCD.
Exceptional Diversity of Allorecognition Receptors in a Nonvertebrate Chordate Reveals Principles of Innate Allelic Discrimination
Rodriguez-Valbuena et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/41129228
Allorecognition—the ability to distinguish self from non-self—is found in many species and is the basis for many processes, such as mate choice, space competition, and immune function. Botryllus schlosseri is a marine invertebrate (a life form lacking a spine) that has many similarities to vertebrates in allorecognition genomic organization and signaling pathways. Researchers used B. schlosseri to investigate allorecognition and identified an unprecedented level of receptor diversity and adaptive ability in the alleles (alternative versions of a gene) used to determine compatibility. These results provide insight into signal processing and allorecognition processes across a broad range of animals. Supported by ORIP (R21OD030520) and NIGMS.