Selected Grantee Publications
- Clear All
- 21 results found
- S10 [SIG, BIG, HEI]
- 2021
Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Tuberculosis/Simian Immunodeficiency Virus Coinfection Model
Sharan et al., Journal of Clinical Investigation. 2021.
https://pubmed.ncbi.nlm.nih.gov/34855621/
In the rhesus macaque model for Mycobacterium tuberculosis plus simian immunodeficiency virus (SIV) co-infection, chronic immune activation rather than depletion of CD4+ T cells correlates with reactivation of latent tuberculosis infection (LTBI). Researchers administered combined antiretroviral therapy (cART) at 2 weeks post-SIV co-infection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival led to better control of viral replication and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. Supported by ORIP (K01OD031898, P51OD011133, P51OD011132, S10OD028653) and NIAID.
An NR2F1-Specific Agonist Suppresses Metastasis by Inducing Cancer Cell Dormancy
Khalil et al., The Journal of Experimental Medicine. 2021.
Researchers described the discovery of a nuclear receptor NR2F1 antagonist that specifically activates dormancy programs in malignant cells. Agonist treatment resulted in a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest in multiple human cell lines, as well as patient-derived organoids. This effect was lost when NR2F1 was knocked out. In mice, agonist treatment resulted in inhibition of lung metastasis of head and neck squamous cell carcinomas, even after cessation of the treatment. This work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis. Supported by ORIP (S10OD018522 and S10OD026880) and others.
Selective G Protein Signaling Driven by Substance P–Neurokinin Receptor Dynamics
Harris et al., Nature Chemical Biology. 2021.
https://www.nature.com/articles/s41589-021-00890-8
Investigators determined the cryogenic-electron microscopy structures of active neurokinin-1 receptor (NK1R) bound to neuropeptide substance P (SP) or the G protein q (Gq)-biased peptide SP6–11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent Gs-signaling but not Gq-signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6–11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. This data unveils the molecular mechanism of how two stimuli (SP and Neurokinin A) yield distinct G protein signaling at the same G protein-coupled receptor. Supported by ORIP (S10OD021741, S10OD020054) and others.
Integrated Spatial Multiomics Reveals Fibroblast Fate During Tissue Repair
Foster et al., PNAS. 2021.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521719/
The function of regenerative medicine in wound healing remains elusive, partially because of how fibroblasts program and respond to injury remains unclear. Investigators presented a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which allowed characterization of cells involved in wound healing across time and space. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, fibroblast epigenomes were imputed with temporospatial resolution. This allowed revelation of potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and reexamination of the canonical phases of wound healing. Supported by ORIP (S10OD018220) and others.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.
A Noncoding RNA Modulator Potentiates Phenylalanine Metabolism in Mice
Li et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/34353949/
The role of long noncoding RNAs (lncRNAs) in phenylketonuria (PKU), an inherited disorder causing build-up of an amino acid causing brain problems, is unknown. Investigators demonstrated that the mouse lncRNA Pair and human lncRNA HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited phenotypes that faithfully models human PKU, such as excessive blood phenylalanine (Phe), growth retardation, and progressive neurological symptoms. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes (i.e., that have the capacity to self-renew by dividing). To develop a strategy for restoring liver lncRNAs, these investigators designed lncRNA mimics that exhibit liver enrichment. Treatment with these mimics reduced excessive Phe in Pair -/- and PAH R408W/R408W mice and improved the Phe tolerance of these mice. Supported by ORIP (S10OD012304) and others.
Sexual Dimorphic Impact of Adult-Onset Somatopause on Life Span and Age-Induced Osteoarthritis
Poudel et al., Aging Cell. 2021.
https://pubmed.ncbi.nlm.nih.gov/?term=Poudel%20SB&cauthor_id=34240807
Osteoarthritis (OA) is a major cause of disability worldwide. In humans, the age-associated decline in growth hormone (GH) levels was hypothesized to play a role in the etiology of OA. Investigators studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity in aged mice. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice. In conclusion, while their life span increased, AOiGHD female mice’s health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity. Supported by ORIP (S10OD010751) and others.
Systems Vaccinology of the BNT162b2 mRNA Vaccine in Humans
Arunachalam et al., Nature . 2021.
https://doi.org/10.1038/s41586-021-03791-x
It was poorly understood how mRNA vaccines against SARS-CoV-2 stimulate protective immune responses. To address this, researchers comprehensively profiled innate and adaptive immune responses of healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in robust production of neutralizing antibodies against wild-type SARS-CoV-2, to a lesser extent, the beta variant, as well as significant increases in antigen-specific polyfunctional CD4+ and CD8+ T cells after the second dose. Booster vaccination stimulated an enhanced innate immune response compared to primary vaccination, demonstrating the capacity of BNT162b2 to prime the innate immune system to mount a more potent response after booster immunization. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
Phase Separation Drives Aberrant Chromatin Looping and Cancer Development
Ahn et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03662-5
How unstructured intrinsically disordered regions (IDRs) contribute to oncogenesis is elusive. Using an Orbitrap fusion tribrid mass spectrometer, investigators show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias, are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad “super-enhancer”-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. This report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumor transformation. Supported by ORIP (S10OD018445).
Tissue-Specific Transcriptional Profiling of Plasmacytoid Dendritic Cells Reveals a Hyperactivated State in Chronic SIV Infection
Lee et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009674
Persistent immune activation is an obstacle to optimal health for people living with HIV. Using RNA sequencing, researchers investigated the immunostimulatory potential of plasmacytoid dendritic cells (pDCs) in chronic SIV infection in rhesus macaques. They observed that pDCs have highly activated profiles in these animals. In contrast, pDCs from SIV-infected sooty mangabeys (natural hosts for SIV) had expression profiles similar to uninfected animals. In chronically infected rhesus macaques, interferon alpha transcripts were readily detected in lymph node-homing pDCs, but not those from blood. Therefore, pDCs are a major producer of type-I interferon in chronic SIV infection and could be a useful immunotherapy target. Supported by ORIP (R24OD010445, P51OD011132, P51OD011092, S10OD026799) and NIAID.