Selected Grantee Publications
Functional Differences Between Rodent and Human PD-1 Linked to Evolutionary Divergence
Masubuchi et al., Science Immunology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39752535/
Programmed cell death protein 1 (PD-1), an immune checkpoint receptor, regulates immunity against cancer. Rodent models (e.g., mice) do not exhibit the same response rates and immune-related adverse effects to PD-1 blocking drugs as patients with cancer. Only 59.6% amino acid sequence identity is conserved in human PD-1 (hu PD-1) and mouse PD-1 (mo PD-1). Researchers used mouse tumor models, coculture assays, and biophysical assays to determine key functional and biochemical differences between hu PD-1 and mo PD-1. HuPD-1 demonstrates stronger suppressive activity of interleukin-2 secretion and CD69 expression than mo PD-1 because of the ectodomain and intracellular domain, but not the transmembrane domain. Analysis of rodent evolution demonstrated that other inhibitory immunoreceptors were positively selected or had selection intensification over PD-1. Understanding the conservation and divergence of PD-1 signaling at the molecular level in humans compared with mice is needed to properly translate preclinical data to clinical therapeutics. Supported by ORIP (S10OD026929), NCI, and NIA.
Single-Cell Transcriptomics Predict Novel Potential Regulators of Acute Epithelial Restitution in the Ischemia-Injured Intestine
Rose et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39853303
Following ischemia in the small intestine, early barrier restoration relies on epithelial restitution to reseal the physical barrier and prevent sepsis. Pigs share a similar gastrointestinal anatomy, physiology, and microbiota with humans. Researchers used neonatal and juvenile, 2- to 6-week-old male and female Yorkshire cross pigs to determine upstream regulators of restitution. Single-cell sequencing of ischemia-injured epithelial cells demonstrated two sub-phenotypes of absorptive enterocytes, with one subset presenting a restitution phenotype. Colony-stimulating factor-1 (CSF1) was the only predicted upstream regulator expressed in juvenile jejunum compared with neonatal jejunum. An in vitro scratch wound assay using IPEC-J2 cells showed that BLZ945, a colony-stimulating factor 1 receptor antagonist, inhibited restitution. Ex vivo ischemia-injured neonatal pig jejunum treated with exogenous CSF1 displayed increased barrier function. This study could inform future research focused on developing novel therapeutics for intestinal barrier injury in patients. Supported by ORIP (T32OD011130, K01OD028207), NCATS, NICHD, and NIDDK.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
The Widely Used Ucp1-Cre Transgene Elicits Complex Developmental and Metabolic Phenotypes
Halurkar et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/39824816
Bacterial artificial chromosome technology is instrumental to mouse transgenics, including in studies of highly thermogenic brown adipose tissue and energy-storing white adipose tissue. Researchers discovered that male and female Ucp1-CreEvdr transgenic mice, which are commonly used to study fat tissue, may have unintended effects on metabolism and development. Findings revealed that these mice show changes in both brown and white fat function and disruptions in gene activity, suggesting broader physiological impacts than previously thought. This study emphasizes the need for careful validation of genetic tools in research to ensure accurate results, highlighting the potential concerns in using the Ucp1-CreEvdr model in metabolic and developmental studies. Supported by ORIP (R21OD034470, R21OD031907) NCATS, NIDCR, and NIDDK.
Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts
Wu et al., Cancer Research Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/39785683
Cancer-associated fibroblasts (CAFs) stimulate the formation and progression of pancreatic adenocarcinoma (PDAC) through the generation of extracellular matrix (ECM). Researchers developed a bispecific antibody (bsAb) that targets α5β1 and αvβ3 integrins expressed on CAFs. Blockade using the bsAb resulted in reduced assembly of fibronectin and collagen fibers in vitro. An antifibrotic effect was observed when CAFs were plated for 72 hours prior to bsAb treatment; pre-deposited ECM was disrupted. Six- to 8-week-old female nu/nu mice treated with bsAb demonstrated fewer tumors and reduced tumor stiffness compared with those exposed to only CAFs co-injected with PDAC cells. These results support a potential novel PDAC therapeutic that targets CAF-mediated fibronectin assembly and ECM production. Supported by ORIP (K01OD030513) and NCI.
Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Reinecke et al., Clinical Cancer Research. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11739783/
The leading cause of deaths in the pediatric osteosarcoma is due to lung metastasis. A current clinical need is the development of therapies that disrupt the later stages of metastasis. Researchers used 6- to 8-week-old female C57BL/6 and CB17-SCID mice to understand how tumor cells disrupt the lung microenvironment to promote tumor growth. Single-cell RNA sequencing and spatial transcriptomics demonstrated osteosarcoma–epithelial cell interactions in a chronic state of wound healing in the lung. Nintedanib administration significantly disrupted metastatic progression compared with the vehicle control, demonstrating a potential novel therapeutic for combating osteosarcoma lung metastasis. Supported by ORIP (K01OD031811), NCI, and NCATS.
Lipid Nanoparticle-Mediated mRNA Delivery to CD34+ Cells in Rhesus Monkeys
Kim et al., Nature Biotechnology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578569
Blood cells, which are derived from hematopoietic stem cells (HSCs), promote pathologies including anemia, sickle cell disease, immunodeficiency, and metabolic disorders when dysfunctional. Because of the morbidity that results from the bone marrow mobilization and chemotherapy patient conditioning of current HSC therapies, novel treatment strategies that deliver RNA to HSCs are needed. Researchers found a lipid nanoparticle (LNP), LNP67, that delivers messenger RNA (mRNA) to murine HSCs in vivo and human HSCs ex vivo without the use of a cKit-targeting ligand. When tested in 7- to 8-month-old male and female rhesus monkeys, LNP67 successfully delivered mRNA to CD34+ cells and liver cells without adverse effects. These results show the potential translational relevance of an in vivo LNP–mRNA drug. Supported by ORIP (U42OD027094, P51OD011107), NIDDK, and NCATS.