Selected Grantee Publications
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- 28 results found
- Cancer
- Rare Diseases
- 2024
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines
Lee et al., International Journal of Molecular Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11432008
Researchers established three new cell lines to model ocular adnexal sebaceous carcinoma (SebCA) and test new therapies. SebCA is a highly problematic periorbital tumor requiring aggressive surgical treatment, and its pathobiology remains poorly understood. With consent from one male and two female patients, tumor tissue was cultured under conditional reprograming, and the cells were analyzed for growth, clonogenicity, apoptosis, and differentiation using methods including western blotting, short tandem repeat profiling, and next-generation sequencing. These newly developed cell lines provide valuable preclinical models for understanding and treating SebCA. Supported by ORIP (K01OD034451).
Impaired Axon Initial Segment Structure and Function in a Model of ARHGEF9 Developmental and Epileptic Encephalopathy
Wang et al., PNAS. 2024.
https://www.pnas.org/doi/10.1073/pnas.2400709121
Researchers developed a mouse model carrying the G55A missense variant identified in ARHGEF9 patients with severe epilepsy and neurodevelopmental phenotypes. Using male Arhgef9G55A mice, this study examined behavioral, molecular, and electrophysiological phenotypes in the Arhgef9G55A model of developmental and epileptic encephalopathies (DEE). Researchers found that the G55A variant causes disruption of inhibitory postsynaptic organization and axon initial segment (AIS) architecture, leading to impairment of both synaptic transmission and action potential generation. The effects of Arhgef9G55A on neuronal function affect both intrinsic and synaptic excitability and preferentially impair AIS. These findings indicate a novel pathological mechanism of DEE and represent a unique example of a neuropathological condition converging from AIS dysfunctions. Supported by ORIP (U54OD020351, U54OD030187, U54OD020351, S10OD026974) and NINDS.
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Bone Marrow Transplantation Increases Sulfatase Activity in Somatic Tissues in a Multiple Sulfatase Deficiency Mouse Model
Presa et al., Communications Medicine. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11502872/pdf/43856_2024_Article_648.pdf
Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder where patients demonstrate loss of function mutations in the SUMF1 gene, resulting in a severe reduction in sulfatase activity. This enzyme deficiency causes impaired lysosomal function and widespread inflammation, leading to clinical manifestations like neurodegeneration, vision and hearing loss, and cardiac disease. The researchers evaluated the therapeutic potential of hematopoietic stem cell transplant (HSCT) to initiate cross-correction, where functional sulfatase enzymes secreted from the healthy donor cells are taken up to restore function in enzyme-deficient host cells. Bone marrow from healthy male and female B6-Sumf1(+/+) mice were transplanted into B6-Sumf1(S153P/S153P) mice, a model for MSD. The results showed that HSCT is suitable to rescue sulfatase activity in peripheral organs, such as the liver, spleen, and heart, but is not beneficial alone in inhibiting the central nervous system pathology of MSD. Supported by ORIP (U54OD020351, U54OD030187, U42OD010921) and NCI.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload
Scholz et al., Cell Transplantation. 2024.
https://journals.sagepub.com/doi/10.1177/09636897241290367
Patients with single-ventricle congenital heart defects suffer from right ventricular pressure overload (RVPO). Researchers developed a novel pulmonary artery banding (PAB) rhesus macaque model to induce RVPO. This study investigated the efficacy of human induced pluripotent stem cell cardiac lineage cell (hiPSC-CL) delivery at low or high dose into adult male and female rhesus macaques with right ventricular dysfunction. The findings indicate that hiPSC-CLs were successfully grafted and integrated to match the surrounding host right ventricle myocardium. These results suggest hiPSC-CL therapy is a potential adjunctive treatment for RVPO, but future research will be needed to elucidate the beneficial effects. Supported by ORIP (P51OD011106).
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
Agca et al., Mammalian Genome. 2024.
https://link.springer.com/article/10.1007/s00335-024-10070-3
The MMRRC has been the nation’s preeminent public repository and distribution archive of mutant mouse models for 25 years. The Consortium, with support from NIH, facilitates biomedical research by identifying, acquiring, evaluating, characterizing, preserving, and distributing a variety of mutant mouse strains to investigators around the world. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8,441 institutions worldwide. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem-cell lines, and murine monoclonal antibodies for nearly 65,000 alleles. The Consortium also provides scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, husbandry, breeding and colony management, and more. Supported by ORIP (U42OD010918, U42OD010924, U42OD010983).