Selected Grantee Publications
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- 38 results found
- Rodent Models
- Neurological
Cannabinoid Receptor 1 Antagonist Genistein Attenuates Marijuana-Induced Vascular Inflammation
Wei et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.04.005
Marijuana use is increasing and is associated with increased risk of cardiovascular disease (CVD); however, the link between marijuana and CVD remains largely unknown. Investigators demonstrated that a psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9‑THC), activates cannabinoid receptor 1 (CB1), causing vascular inflammation, oxidative stress, endothelial dysfunction, and atherosclerosis. This in silico virtual screening study suggested that genistein, a soybean isoflavone, would be a putative CB1 antagonist. Their validation study showed that in male mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. This study for the first time revealed that genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis while preserving clinically useful effects. Supported by ORIP (S10OD030452) and others.
AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
Goertsen et al., Nature Neuroscience. 2021.
https://www.nature.com/articles/s41593-021-00969-4
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.
Neuropeptide S Receptor 1 is a Nonhormonal Treatment Target in Endometriosis
Tapmeier et al., Science Translational Medicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34433639
Investigators analyzed genetic sequences of humans (n=32 families) and pedigree rhesus macaques (n=849) with spontaneous endometriosis to uncover potential targets for treatment. Target associations indicated a common insertion/deletion variant in NPSR1, the gene encoding neuropeptide S receptor 1. Immunocytochemistry, RT-PCR, and flow cytometry experiments indicated NPSR1 was expressed in the glandular epithelium of eutopic and ectopic endometrium. In a mouse model for endometriosis, an inhibitor of NPSR1-mediated signaling blocked proinflammatory TNFα release, monocyte chemotaxis, and inflammatory cell infiltrate. Further studies in nonhuman primates are needed; however, these results provide support for a nonhormonal treatment of endometriosis. Supported by ORIP (R24OD011173, P51OD011106).
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.
The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders
Subburaju et al., ACS Chemical Neuroscience. 2021.
https://pubs.acs.org/doi/full/10.1021/acschemneuro.1c00094
The dopamine D2 receptor exists in two different states, D2high and D2low; the former is the functional form of the D2 receptor and associates with intracellular G-proteins. The D2 agonist [3H]MCL-536 has high affinity for the D2 receptor (Kd 0.8 nM) and potently displaces the binding of (R-(-)-N-n-propylnorapomorphine (NPA; Ki 0.16 nM) and raclopride (Ki 0.9 nM) in competition binding assays. The authors characterized [3H]MCL-536. [3H]MCL-536 as metabolically stable. In vitro autoradiography on transaxial and coronal brain sections showed specific binding of [3H]MCL-536. [3H]MCL-536's unique properties make it a valuable tool for research on neurological disorders like Parkinson's disease or schizophrenia. Supported by ORIP (R43OD020186, R44OD024615) and NIMH.
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.
Lipocalin-2 Is an Anorexigenic Signal in Primates
Petropoulou et al., eLife. 2020.
https://doi.org/10.7554/eLife.58949
The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity. Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, and NHLBI.