Selected Grantee Publications
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- 57 results found
- Neurological
- Genetics
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.
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.
Evidence in Primates Supporting the Use of Chemogenetics for the Treatment of Human Refractory Neuropsychiatric Disorders
Roseboom et al., Molecular Therapy. 2021.
https://doi.org/10.1016/j.ymthe.2021.04.021
A rhesus macaque model for pathological anxiety was used to investigate the feasibility of decreasing anxiety using chemogenetics, known as DREADDs (designer receptors exclusively activated by designer drugs), to reduce amygdala neuronal activity. A low-dose clozapine administration strategy was developed to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in the chemogentic monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology. Supported by ORIP (P51OD011106), NIMH, and NICHD.
Bilateral Visual Projections Exist in Non-Teleost Bony Fish and Predate the Emergence of Tetrapods
Vigouroux et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/33833117/
In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here, Vigouroux et al. showed that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral projections does not correlate with terrestrial transition or predatory behavior. However, overexpression of human ZIC2 induces ipsilateral visual projections in zebrafish. Therefore, the existence of bilateral visual projections likely preceded the emergence of binocular vision in tetrapods. Supported by ORIP (R01OD011116).
Interneuron Origins in the Embryonic Porcine Medial Ganglionic Eminence
Casalia et al., Journal of Neuroscience. 2021.
https://pubmed.ncbi.nlm.nih.gov/33637558/
The authors report that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents. Their findings reveal that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies. They demonstrate that porcine medial ganglionic eminence exhibits a distinct transcriptional and interneuron-specific antibody profile, in vitro migratory capacity, and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic interneuron origins in the pig; because a rich neurodevelopmental literature on embryonic mouse medial ganglionic eminence exists (with some additional characterizations in monkeys and humans), their work allows direct neurodevelopmental comparisons with this literature. Supported by ORIP (U42OD011140) and NINDS.
Trim-Away Mediated Knock Down Uncovers a New Function for Lbh During Gastrulation of Xenopus laevis
Weir et al., Developmental Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/33159936/
The protein Lbh was identified as necessary for cranial neural crest cell migration in Xenopus. To investigate its role in embryonic events, the authors employed the technique "Trim-Away" to degrade this maternally deposited protein. Trim-Away utilizes the E3 ubiquitin ligase trim21 to degrade proteins targeted with an antibody. Early knockdown of Lbh in Xenopus results in defects in gastrulation that present with a decrease in fibronectin matrix assembly, an increase in mesodermal cell migration and decrease in endodermal cell cohesion. The technique is also effective on a second abundant maternal Protein Kinase C And Casein Kinase Substrate In Neurons 2. Supported by ORIP (R24OD021485) and NIDCR.
Endogenous Zebrafish Neural Cre Drivers Generated by CRISPR/Cas9 Short Homology Directed Targeted Integration
Almeida et al., Scientific Reports. 2021.
https://pubmed.ncbi.nlm.nih.gov/33462297/
Almeida et al. previously reported precision targeted integration of reporter DNA in zebrafish using CRISPR/Cas9. Here, they isolated zebrafish Cre recombinase drivers. A 2A-Cre recombinase transgene with 48 bp homology arms was targeted into proneural genes ascl1b, olig2 and neurod1. They observed high rates of germline transmission from 10 to 100% (10% olig2; 20% neurod1; 100% ascl1b). The lines Tg(ascl1b-2A-Cre)is75, Tg(olig2-2A-Cre)is76, and Tg(neurod1-2A-Cre)is77 expressed functional Cre recombinase in the cell populations. Results demonstrate Cre recombinase expression is driven by the native promoter and regulatory elements of targeted genes. This approach is a cost-effective method to generate cell type specific zebrafish Cre and CreERT2 drivers. Supported by ORIP (R24OD020166).