Selected Grantee Publications
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- niaid
- Neurological
- Genetics
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.
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
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.
Interferon Regulatory Factor 7 Modulates Virus Clearance and Immune Responses to Alphavirus Encephalomyelitis
Troisi et al., Journal of Virology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37772825/
Interferon regulatory factor 7 (IRF7)–deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7-/- mice produce low levels of IFN-α but high levels of IFN-β with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7-/- mice developed inflammation earlier but failed to clear virus from motor neuron–rich regions of the brainstem and spinal cord. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance. Supported by ORIP (T32OD011089, R01OD01026529) NINDS, and NIAID.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis
Moley et al., American Journal of Pathology. 2023.
https://www.sciencedirect.com/science/article/pii/S0002944023001980?via%3Dihub=
Brucellosis is a globally significant zoonotic disease. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. Following pulmonary infection with B. melitensis, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Transcriptional analysis of Brucella-infected brains revealed marked upregulation of genes associated with inflammation and interferon responses. Collectively, these findings indicate that ILCs and interferons play an important role in prevention of focal complications during Brucella infection and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis. Supported by ORIP (T32OD011126) and NIAID.