Selected Grantee Publications
Cannabinoid Control of Gingival Immune Activation in Chronically SIV-Infected Rhesus Macaques Involves Modulation of the Indoleamine-2,3-Dioxygenase-1 Pathway and Salivary Microbiome
McDew-White et al., EBioMedicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34954656/
HIV-associated periodontal disease (PD) affects people living with HIV (PLWH) on combination anti-retroviral therapy (cART). Researchers used a systems biology approach to investigate the molecular, metabolome, and microbiome changes underlying PD and its modulation by phytocannabinoids (Δ9-THC) in rhesus macaques. Δ9-THC reduced IDO1 protein expression. The findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis, and potentially metabolic disease in PLWH on cART. Supported by ORIP (P51OD011104, P51OD011133, U42OD010442), NIAID, NIDA, NIDDK, NIDCR, and NIMH.
Deep Learning Is Widely Applicable to Phenotyping Embryonic Development and Disease
Naert et al., Development. 2021.
https://pubmed.ncbi.nlm.nih.gov/34739029/
Genome editing simplifies the generation of new animal models for congenital disorders. The authors illustrate how deep learning (U-Net) automates segmentation tasks in various imaging modalities. They demonstrate this approach in embryos with polycystic kidneys (pkd1 and pkd2) and craniofacial dysmorphia (six1). They provide a library of pre-trained networks and detailed instructions for applying deep learning to datasets and demonstrate the versatility, precision, and scalability of deep neural network phenotyping on embryonic disease models. Supported by ORIP (P40OD010997, R24OD030008), NICHD, NIDDK, and NIMH.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
Western-Style Diet Consumption Impairs Maternal Insulin Sensitivity and Glucose Metabolism During Pregnancy in a Japanese Macaque Model
Elsakr et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-92464-w
Using a Japanese macaque model, investigators assessed the metabolic effects of obesity and a calorically dense, Western-style diet (WSD; 36.3% fat), either alone or together, on maternal glucose tolerance and insulin levels in dams during pregnancy (n = 95 females followed over multiple pregnancies [n = 273]). With prolonged WSD feeding, multiple diet switches, and/or increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. The results suggest that prolonged or recurrent calorically dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. Supported by ORIP (P51OD011092), NIDDK and NIMH.
Rhesus Macaques Build New Social Connections After a Natural Disaster
Testard et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221003687
Climate change has increased the frequency and intensity of weather-related disasters such as hurricanes and floods. In 2017, Puerto Rico suffered its worst natural disaster, Hurricane Maria, leaving 3,000 dead and provoking a mental health crisis. Cayo Santiago Island, home to a population of rhesus macaques (Macaca mulatta), was devastated by this storm. Testard et al. compared social networks of two groups of macaques before and after the hurricane and found an increase in affiliative social connections, driven largely by monkeys most socially isolated before Hurricane Maria. Further analysis revealed monkeys invested in building new relationships rather than strengthening existing ones. Supported by ORIP (P40OD012217), NIA, and NIMH.
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.
Creb5 Establishes the Competence for Prg4 Expression in Articular Cartilage
Zhang et al., Communications Biology. 2021.
https://doi.org/10.1038/s42003-021-01857-0
Cells comprising the superficial zone of articular cartilage express lubricin, encoded by the Prg4 gene, that lubricates joints. Researchers identified Creb5 as a transcription factor that is required for TGF-β and EGFR signaling to induce Prg4 expression. Forced expression of Creb5 in deep-zone chondrocytes of articular cartilage confers competence for TGF-β and EGFR signals to induce Prg4 expression. The researchers showed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, which work together with a more distal regulatory element to drive induction of Prg4 by TGF-β. Thus, Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage. Supported by ORIP (U42OD11158), NIAMS, and NIDDK.
A Chromosome-Level Genome of Astyanax mexicanus Surface Fish for Comparing Population-Specific Genetic Differences Contributing to Trait Evolution
Warren et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33664263/
Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic (morphological adaptation of an animal to living in the constant darkness of caves) traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Warren et al. present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, they performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss (dusp26). They also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species. Supported by ORIP (R24OD011198), NIA, NICHD, NIGMS, amd NIDCR.