Selected Grantee Publications
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.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
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.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Systematic Multi-trait AAV Capsid Engineering for Efficient Gene Delivery
Eid et al., Nature Communications. 2024.
https://doi.org/10.1038/s41467-024-50555-y
Engineering novel functions into proteins while retaining desired traits is a key challenge for developers of viral vectors, antibodies, and inhibitors of medical and industrial value. In this study, investigators developed Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait adeno-associated virus (AAV) capsids. Fit4Function was used to generate reproducible screening data from a capsid library that samples the entire manufacturable sequence space. The Fit4Function data were used to train accurate sequence-to-function models, which were combined to develop a library of capsid candidates. Compared to AAV9, top candidates from the Fit4Function capsid library exhibited comparable production yields; more efficient murine liver transduction; up to 1,000-fold greater human hepatocyte transduction; and increased enrichment in a screen for liver transduction in macaques. The Fit4Function strategy enables prediction of peptide-modified AAV capsid traits across species and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits. Supported by ORIP (P51OD011107, U42OD027094), NIDDK, NIMH, and NINDS.
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.