Selected Grantee Publications
Exosome Cell Origin Affects In Vitro Markers of Tendon Repair in Ovine Macrophages and Tenocytes
von Stade et al., Tissue Engineering Part A. 2023.
https://pubmed.ncbi.nlm.nih.gov/36792933/
The underlying pathogenesis of rotator cuff tendinopathy reflects a combination of intrinsic and extrinsic factors, and recent work suggests that cell-to-cell communication drives the severity of tendon changes. Researchers are interested in the role of extracellular vesicles in tendon mechanical resilience, tissue organization, and anti-inflammatory macrophage phenotype predominance in response to tendon injury. In this study, investigators demonstrated how exosomes differ functionally based on cell source. This work suggests that control of exosome composition could lead to more effective therapies for certain tissues. Supported by ORIP (K01OD022982) and NCATS.
Lipid Droplets and Peroxisomes Are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids
Papsdorf et al., Nature Cell Biology. 2023.
https://www.nature.com/articles/s41556-023-01136-6
Investigators studied the mechanism by which mono-unsaturated fatty acids (MUFAs) extend longevity. They found that MUFAs upregulated the number of lipid droplets in fat storage tissues of Caenorhabditis elegans, and increased lipid droplets are necessary for MUFA-induced longevity and predicted remaining lifespan. Lipidomics data revealed that MUFAs modify the ratio of membrane lipids and ether lipids, which leads to decreased lipid oxidation in middle-aged individuals. MUFAs also upregulate peroxisome number. A targeted screen revealed that induction of both lipid droplets and peroxisomes is optimal for longevity. This study opens new interventive avenues to delay aging. Supported by ORIP (S10OD025004, S10OD028536, P40OD010440), NIA, NCCIH, NIDDK, and NHGRI.
Allelic Strengths of Encephalopathy-Associated UBA5 Variants Correlate Between In Vivo and In Vitro Assays
Pan et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37502976/
The UBA5 gene is associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder, in humans. The link between UBA5 variants and severity of DEE44, however, is not established. Investigators developed humanized fly models carrying a series of patient UBA5 variants. These flies showed differences in survival rates, developmental progress, life span, and neurological well-being. The severity of these defects correlated strongly with functional defects of UBA5 variants, allowing the classification of UBA5 loss-of-function variants into mild, intermediate, and severe allelic strengths in patients. This study provides resources for systematic investigation of the mechanistic link between UBA5 variants and DEE44 and for developing diagnostic approaches. Supported by ORIP (R24OD022005, R24OD031447, U54OD035865) and NCATS.
Host-Derived Growth Factors Drive ERK Phosphorylation and MCL1 Expression to Promote Osteosarcoma Cell Survival During Metastatic Lung Colonization
McAloney et al., Cellular Oncology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37676378/
Mortality from osteosarcoma is closely linked to lung metastasis, even though the lung appears to be a hostile environment for tumor cells. Using female mice, researchers assessed changes in both host and tumor cells during colonization. Their findings suggest that the mitogen-activated protein kinase (MAPK) pathway is significantly elevated in early and established metastases, which correlates with expression of anti-apoptotic genes (e.g., MCL1). The authors conclude that niche-derived growth factors drive increased MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. This gene is a promising target for future therapeutic development. Supported by ORIP (K01OD031811), NCI, and NCATS.
Whole Genome Analysis for 163 gRNAs in Cas9-Edited Mice Reveals Minimal Off-Target Activity
Peterson et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04974-0
CRISPR/Cas9 genome editing offers potential as a treatment for genetic diseases in humans. Using whole-genome sequencing, investigators assessed the occurrence of Streptococcus pyogenes Cas9–induced off-target mutagenesis in Cas9-edited founder mice. Sequencing and computational analysis indicate that the risk of Cas9 cutting at predicted off-target sites is lower than random genetic variation introduced into the genomes of inbred mice through mating. These findings will inform future design and use of Cas9-edited animal models and can provide context for evaluating off-target potential in genetically diverse patient populations. Supported by ORIP (UM1OD023221, UM1OD023222) and NHGRI.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
Effects of Acute Femoral Head Ischemia on the Growth Plate and Metaphysis in a Piglet Model of Legg-Calvé-Perthes Disease
Armstrong et al., Osteoarthritis and Cartilage. 2023.
https://pubmed.ncbi.nlm.nih.gov/36696941/
Legg-Calvé-Perthes disease (LCPD) can lead to permanent deformity of the femoral head and premature osteoarthritis, but the underlying cause remains unknown. More work is needed to determine optimal treatment methods for LCPD. Using a piglet model for LCPD, researchers assessed the effects of acute femoral head ischemia on the proximal femoral growth plate and metaphysis. They reported that alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. These findings suggest that growth disruption may occur sooner after the onset of ischemia than researchers had hypothesized previously. Supported by ORIP (T32OD010993, K01OD021293), NIAMS, and NCATS.
Resolution of Structural Variation in Diverse Mouse Genomes Reveals Chromatin Remodeling due to Transposable Elements
Ferraj et al., Cell Genomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203049/
Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. Here, investigators used long-read whole genome sequencing to assemble the genomes of 20 diverse inbred laboratory strains of mice. From whole-genome comparisons, they generated a sequence-resolved callset of 413,758 structural variants. These data are presented as a comprehensive resource that can be used for future genomic studies, aid in modeling and studying the effects of genetic variation, and enhance genotype-to-phenotype research. Supported by ORIP (R24OD021325), NCI, NIGMS, and NHGRI.
Topologically Associating Domain Boundaries Are Required for Normal Genome Function
Rajderkar et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04819-w
Eukaryotic genomes fold into topologically associating domains (TADs), sub-megabase-scale chromatin segments characterized by high intra-domain chromatin contact frequency. Investigators selected eight independent TAD boundaries in the vicinity of genes active during embryonic development, individually deleted these boundaries from the mouse genome, and systematically examined the consequences on survival, genome organization, gene expression, and development. Results of the studies demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to consider the potential pathogenicity of deletions affecting TAD boundaries in clinical genetics screening. Supported by ORIP (UM1OD023221), NIGMS, and NHGRI.
Late Gene Expression–Deficient Cytomegalovirus Vectors Elicit Conventional T Cells That Do Not Protect Against SIV
Hansen et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070102/
Cytomegalovirus (CMV)–based vaccines aim to exploit unique immunological adaptations, including host manipulation and immune evasion strategies. Translating CMV-based vaccines from rhesus macaques to humans requires translating the immune factors responsible for efficacy, as well as vaccine vectors that are sufficiently safe for widespread use. Researchers examined the impact of a stringent attenuation strategy on vector-induced immune protection against simian immunodeficiency virus (SIV) in rhesus macaques of both sexes. They reported that elicited CD8+ T cells exclusively failed to protect against SIV challenge. These data suggest that late viral gene expression and/or residual in vivo spreading are required to induce protective CD8+ T cell responses. Supported by ORIP (P51OD011092, P51OD011107, S10OD016261), NCI, NIAID, and NCATS.