Selected Grantee Publications
Two Neuronal Peptides Encoded from a Single Transcript Regulate Mitochondrial Complex III in Drosophila
Bosch et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.82709
Transcripts with small open-reading frames (smORFs) are underrepresented in genome annotations. Functions of peptides encoded by smORFs are poorly understood. The investigators systematically characterized human-conserved smORF genes in Drosophila and found two peptides, Sloth1 and Sloth2, that are highly expressed in neurons. They showed that Sloth1 and Sloth2 are paralogs with high sequence similarity but are not functionally redundant. Loss of either peptide resulted in lethality, impaired mitochondrial function, and neurodegeneration. This work suggests the value of phenotypic analysis of smORFs using Drosophila as a model. Supported by ORIP (R24OD019847), NHGRI, and NIGMS.
Long-Term Evolutionary Adaptation of SIVcpz toward HIV-1 Using a Humanized Mouse Model
Schmitt et al., Journal of Medical Primatology. 2022.
https://www.doi.org/10.1111/jmp.12616
Chimpanzee-derived simian immunodeficiency viruses (SIVcpz) are thought to have evolved into the highly pathogenic HIV-1 Group M, but the genetic adaptations required for SIV progenitor viruses to become pathogenic and established as HIVs in the human population have remained unclear. Using humanized mice of both sexes, researchers mimicked the evolution of SIVcpz into HIV-1 Group M through serial passaging. After four generations, the researchers observed increased initial viral load, increased CD4+ T cell decline, and nonsynonymous substitutions. Overall, these data indicate increased viral fitness and pathogenicity. This work also demonstrates the utility of humanized mice in recreating the adaptive pressures necessary for the evolution of SIVcpz into HIV-1. Supported by ORIP (P51OD011104, P51OD011106), NCATS, and NIAID.
Mendelian Gene Identification through Mouse Embryo Viability Screening
Cacheiro et al., Genome Medicine. 2022.
https://www.doi.org/10.1186/s13073-022-01118-7
The investigators dissected phenotypic similarities between patients and model organisms by assessing the embryonic stage at which homozygous loss of function results in lethality in mice of both sexes obtained from the International Mouse Phenotyping Consortium. Information on knockout mouse embryo lethality can be used to prioritize candidate genes associated with certain disorders. Access to unsolved cases from rare-disease genome sequencing programs allows for the screening of those genes for potentially pathogenic variants, which could lead to a diagnosis and new potential treatment options to inform the management of human disease. Supported by ORIP (UM1OD023221, UM1OD023222, U42OD011174) and NHGRI.
Promoting Validation and Cross-Phylogenetic Integration in Model Organism Research
Cheng et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049600
Model organisms are essential for biomedical research and therapeutic development, but translation of such research to the clinic is low. The authors summarized discussions from an NIH virtual workshop series, titled “Validation of Animal Models and Tools for Biomedical Research,” held from 2020 to 2021. They described challenges and opportunities for developing and integrating tools and resources and provided suggestions for improving the rigor, validation, reproducibility, and translatability of model organism research. Supported by ORIP (R01OD011116, R24OD031447, R03OD030597, R24OD018559, R24OD017870, R24OD026591, R24OD022005, U42OD026645, U42OD012210, U54OD030165, UM1OD023221, P51OD011107), NIAMS, NIDDK, NIGMS, NHGRI, and NINDS.
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
Recreating the Heart’s Helical Structure–Function Relationship With Focused Rotary Jet Spinning
Chang et al., Science. 2022.
https://www.doi.org/10.1126/science.abl6395
The investigators developed a tissue engineering approach that enables rapid deposition of cardiomyocyte microfibers with programmable alignments in 3D geometries. Using this focused rotary jet spinning (FRJS) method, they reproduced tissue scaffolds with contractile cells' helical alignments, resembling complex structures of the musculature and properties of a natural heart. This work represents an important advance towards biofabrication of tissue models for healthy and diseased hearts by manipulating orientation of specific fibers. With the technological advancement over other competing methods, FRJS might provide a pathway towards fabricating other tissues and organs with diverse cell populations. Supported by ORIP (S10OD023519) and NCATS.
A Novel DPH5-Related Diphthamide-Deficiency Syndrome Causing Embryonic Lethality or Profound Neurodevelopmental Disorder
Shankar et al., Genetics in Medicine. 2022.
https://www.doi.org/10.1016/j.gim.2022.03.014
Neurodevelopmental disorders (NDDs) affect more than 3% of the pediatric population and often have associated neurologic or multisystem involvement. The underlying genetic etiology of NDDs remains unknown in many individuals. Investigators characterized the molecular basis of NDDs in children of both sexes with nonverbal NDDs from three unrelated families with distinct overlapping craniofacial features. The investigators also used a mouse model of both sexes to determine the pathogenicity of variants of uncertain significance, as well as genes of uncertain significance, to advance translational genomics and provide precision health care. They identified several variants in DPH5 as a potential cause of profound NDD. Their findings provide strong clinical, biochemical, and functional evidence for DPH5 variants as a novel cause of embryonic lethality or profound NDD with multisystem involvement. Based on these findings, the authors propose that “DPH5-related diphthamide deficiency syndrome” is a novel autosomal-recessive Mendelian disorder. Supported by ORIP (K01OD026608, U42OD012210) and NHGRI.
Innate Immune Regulation in HIV Latency Models
Olson et al., Retrovirology. 2022.
https://www.doi.org/10.1186/s12977-022-00599-z
Researchers are interested in developing therapeutic approaches to target latent HIV reservoirs, which are unaffected by antiretroviral therapy. Previous studies suggest that HIV latency might be related to viral RNA sensing, interferon (IFN) signaling, and IFN-stimulated gene (ISG) activation. In this study, the researchers evaluated responses to stimulation by retinoic acid–inducible gene I agonists and IFN in multiple CD4+ T cell line models for HIV latency. The models represented various aspects of latent infection and viral control. Several of the cell lines demonstrated reduced ISG induction, suggesting that long-term latency might be related to dysregulation of the downstream IFN response. These effects likely reflect transcriptional changes occurring within a core set of ISGs and altering IFN responses. Additional studies could provide insight into the functions of these ISGs in HIV latency. Supported by ORIP (P51OD010425), NCATS, and NIAID.
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.
The Early Life Microbiota Mediates Maternal Effects on Offspring Growth in a Nonhuman Primate
Petrullo et al., iScience. 2022.
https://www.doi.org/10.1016/j.isci.2022.103948
Mammalian mothers influence offspring development by providing nutrients and other bioactive compounds through the placenta or milk. A relatively unexplored mechanism for maternal effects is vertical transmission of bacteria through milk to the infant gut. Infants that receive more glycan-utilizing bacteria from milk might better exploit oligosaccharides, which could improve nutrition and accelerate growth. Researchers found that first-time vervet mothers harbored a milk bacterial community that was less diverse due to the dominance of Bacteroides fragilis, a glycan-utilizing bacteria. These low-parity females had infants that grew faster, suggesting that vertical transmission of bacteria via milk can mediate maternal effects on growth. These results indicate non-nutritive milk constituents play important roles in development. Commercial milk formula might need to be improved or supplemented to better support infant health. Supported by ORIP (P40OD010965) and NCATS.