Selected Grantee Publications
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Pathogenesis and Virulence of Coronavirus Disease: Comparative Pathology of Animal Models for COVID-19
Kirk et al., Virulence. 2024.
https://pubmed.ncbi.nlm.nih.gov/38362881
Researchers have used animal models that can replicate clinical and pathologic features of severe human coronavirus infections to develop novel vaccines and therapeutics in humans. The purpose of this review is to describe important animal models for COVID-19, with an emphasis on comparative pathology. The highlighted species included mice, ferrets, hamsters, and nonhuman primates. Knowledge gained from studying these animal models can help inform appropriate model selection for disease modeling, as well as for vaccine and therapeutic developments. Supported by ORIP (T32OD010993) and NIAID.
Intestinal Epithelial Adaptations to Vertical Sleeve Gastrectomy Defined at Single-Cell Resolution
Koch-Laskowski et al., Genomics. 2024.
https://pubmed.ncbi.nlm.nih.gov/38309446/
Perturbations in the intestinal epithelium have been linked to the pathogenesis of metabolic disease. Bariatric procedures, such as vertical sleeve gastrectomy (VSG), cause gut adaptations that induce robust metabolic improvements. Using a male mouse model, the authors assessed the effects of VSG on different cell lineages of the small intestinal epithelium. They show that Paneth cells display increased expression of the gut peptide Reg3g after VSG. Additionally, VSG restores pathways pertaining to mitochondrial respiration and cellular metabolism, especially within crypt-based cells. Overall, this work demonstrates how adaptations among specific cell types can affect gut epithelial homeostasis; these findings can help researchers develop targeted, less invasive treatment strategies for metabolic disease. Supported by ORIP (F30OD031914), NCI, and NIDDK.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Nayyer et al., Clinical Cancer Research. 2024.
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. In this study, investigators evaluated the efficacy of combining CDKi (abemaciclib) and anti–PD-1 therapy (“combination therapy”) in mouse models for brain metastases, elucidated how combination therapy remodeled the tumor–immune microenvironment (TIME) and T-cell receptor (TCR) repertoires, and investigated the effects of CDKi on T-cell development and maintenance in NOD-scid Il2rgnull (NSG) mice engrafted with human immune systems (“humanized mice”). Results offer a strong rationale for the clinical evaluation of combination CDKi and PD-1 blockade in patients with brain metastases. Supported by ORIP (R24OD026440), NCI, and NIAID.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Zilberg et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-023-44601-4
The authors reported the cryogenic electron microscopy structure of human trace amine-associated receptor 1 (hTAAR1, hTA1) signaling complex, a key modulator in monoaminergic neurotransmission, as well as its similarities and differences with other TAAR members and rodent TA1 receptors. This discovery has elucidated hTA1’s molecular mechanisms underlining the strongly divergent pharmacological properties of human and rodent TA1 and therefore will boost the translation of preclinical studies to clinical applications in treating disorders of dopaminergic dysfunction, metabolic disorders, cognitive impairment, and sleep-related dysfunction. Supported by ORIP (S10OD019994, S10OD026880, and S10OD030463), NIDA, NIGMS, NIMH, and NCATS.
GenomeMUSter Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration and Analysis
Ball et al., Genome Research. 2024.
https://genome.cshlp.org/content/34/1/145.long
Advances in genetics, including transcriptome-wide and phenome-wide association analysis methods, create compelling new opportunities for using fully reproducible and widely studied inbred mouse strains to characterize the polygenetic basis for individual differences in disease-related traits. Investigators developed an imputation approach and implemented data service to provide a broad and more comprehensive mouse variant resource. They evaluated the strain-specific imputation accuracy on a “held-out” test set that was not used in the imputation process. The authors present its application to multipopulation and multispecies analyses of complex trait variation in type 2 diabetes and substance use disorders and compare these results to human genetics studies. Supported by ORIP (U42OD010921, P40OD011102, R24OD035408), NCI, NIAAA, NIDA, and NIDCD.
A Single-Cell Time-Lapse of Mouse Prenatal Development From Gastrula to Birth
Qiu et al., Nature. 2024.
https://pubmed.ncbi.nlm.nih.gov/38355799/
In this study, investigators combined single-cell transcriptome profiling of male and female mouse embryos and newborn pups with previously published data to construct a tree of cell-type relationships tracing development from zygote to birth. They applied optimized single-cell combinatorial indexing to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation to birth; establish a global framework for exploring mammalian development; and construct a rooted tree of cell-type relationships, from zygote to birth. Their analysis allowed them to systematically nominate genes that encode transcription factors and other proteins as candidate drivers of the in vivo differentiation of hundreds of cell types. Extending this framework to postnatal time points could yield a single-cell time-lapse of the entire mammalian life span, from conception to death. Supported by ORIP (UM1OD023222) and NHGRI.
Newly Identified Roles for PIEZO1 Mechanosensor in Controlling Normal Megakaryocyte Development and in Primary Myelofibrosis
Abbonante et al., American Journal of Hematology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38165047/
Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation are only partially understood. The authors report that PIEZO1, a mechanosensitive cation channel, is expressed in mouse and human Mks, and activation of PIEZO1 increased the number of immature Mks in mice. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Together, these data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation might contribute to aggravating disease. Supported by ORIP (K01OD025290), NHGRI, NHLBI, and NCATS.
Conduction-Dominated Cryomesh for Organism Vitrification
Guo et al., Advanced Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/38018294/
Vitrification-based cryopreservation via cryomesh is a promising approach for maintaining biodiversity, health care, and sustainable food production via long-term preservation of biological systems. Here, researchers conducted a series of experiments aimed at optimizing the cooling and rewarming rates of cryomesh to increase the viability of various cryopreserved biosystems. They found that vitrification was significantly improved by increasing thermal conductivity, reducing mesh wire diameter and pore size, and minimizing the nitrogen vapor barrier of the conduction-dominated cryomesh. Cooling rates increased twofold to tenfold in a variety of biosystems. The conduction-dominated cryomesh improved the cryopreservation outcomes of coral larvae, Drosophila embryos, and zebrafish embryos by vitrification. These findings suggest that the conduction-dominated cryomesh can improve vitrification in such biosystems for biorepositories, agriculture and aquaculture, and research. Supported by ORIP (R24OD028444, R21OD028758, R24OD034063, R21OD028214), NIDDK, and NIGMS.
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
Cruz Cisneros et al., Vaccines. 2024.
https://pubmed.ncbi.nlm.nih.gov/38276675/
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. Although host genetic factors are known to affect vaccine efficacy for such respiratory pathogens as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. Investigators used the diversity outbred mouse model to study the effects of genetic variation on vaccine efficiency. Data indicate that variations in vaccine response in mice are heritable, similar to that in human populations. Supported by ORIP (U42OD010924), NIAID, and NIGMS.