Selected Grantee Publications
Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys
Tao et al., Nature Medicine. 2021.
https://www.nature.com/articles/s41591-021-01257-1
Generation of induced pluripotent stem cells (iPSCs) enables standardized of dopamine (DA) neurons for autologous transplantation therapy to improve motor functions in Parkinson disease (PD). Adult male rhesus PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs of PD over a 2-year period without immunosuppressive therapy. Mathematical modeling showed correlations between surviving DA neurons with PET signal intensity and behavior recovery regardless of autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number. The results demonstrate favorable efficacy of the autologous transplant approach to treat PD. Supported by ORIP (P51OD011106) NINDS, and NICHD.
Acoustofluidic Rotational Tweezing Enables High-Speed Contactless Morphological Phenotyping of Zebrafish Larvae
Chen et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33602914/
These authors demonstrate an acoustofluidic rotational tweezing platform that enables contactless, high-speed, 3D multispectral imaging and digital reconstruction of zebrafish larvae for quantitative phenotypic analysis. The acoustic-induced polarized vortex streaming achieves contactless and rapid (~1 s/rotation) rotation of zebrafish larvae enabling multispectral imaging of the zebrafish body and internal organs. They developed a 3D reconstruction pipeline that yields accurate 3D models based on the multi-view images for quantitative evaluation. With its contactless nature and advantages in speed and automation, the acoustofluidic rotational tweezing system has the potential to be a valuable asset for developmental biology and pre-clinical drug development in pharmacology. Supported by ORIP (R43OD024963), NCI, and NIGMS.
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Gramatica et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.02393-20
Activation of latent HIV-1 expression could benefit many HIV cure strategies. Researchers evaluated two AKT/mTOR activators, SB-216763 and tideglusib, as a potential new class of LRAs. The drugs reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy without causing T cell activation or impaired effector function of cytotoxic T lymphocytes or NK cells. When tested in vivo in monkeys, tideglusib showed unfavorable pharmacodynamic properties and did not reverse SIV latency. The discordance between the ex vivo and in vivo results underscores the importance of developing novel LRAs that allow systemic drug delivery to relevant anatomical compartments. Supported by ORIP (P51OD011092), NIAID, NIGMS, NIMH, and NCI.
A Modular Master Regulator Landscape Controls Cancer Transcriptional Identity
Paul et al., Cell. 2021.
https://www.sciencedirect.com/science/article/pii/S0092867420316172
The mechanisms linking genomic alterations to transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, MR block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations. Supported by ORIP (S10OD012351 and S10OD021764) and NCI.
Increased Proviral DNA in Circulating Cells Correlates With Plasma Viral Rebound in SIV-Infected Rhesus Macaques after Antiretroviral Therapy Interruption
Ziani et al., Journal of Virology. 2021.
https://jvi.asm.org/content/early/2021/01/05/JVI.02064-20
Investigators longitudinally tracked dynamic decay of cell-associated viral RNA/DNA in systemic and lymphoid tissues in SIV-infected rhesus macaques on prolonged combined antiretroviral therapy (cART) to evaluate predictors of viral rebound after treatment cessation. Suppressive cART substantially reduced plasma SIV RNA, cell-associated unspliced, and multiply spliced SIV RNA to undetectable levels, yet viral DNA remained detectable in systemic tissues and lymphoid compartments throughout cART. A rapid increase of integrated proviral DNA in peripheral mononuclear cells was detected once cART was withdrawn, accompanied by the emergence of detectable plasma viral load. The increase of peripheral proviral DNA post cART interruption correlated with the emergence and degree of viral rebound. These results suggest that measuring total viral DNA in SIV infection may be a relatively simple surrogate marker of reservoir size, and may predict viral rebound after treatment interruption, and inform treatment strategies. Supported by ORIP (P51OD011104), NIAID and NICHD.
Antibody-Mediated Depletion of Viral Reservoirs is Limited in SIV-Infected Macaques Treated Early With Antiretroviral Therapy
Swanstrom et al., Journal of Clinical Investigation. 2021.
https://doi.org/10.1172/JCI142421
Virus-specific strategies to target the latent HIV reservoir in individuals on combination antiretroviral therapy (cART) have been limited by inefficient induction of viral protein expression. Researchers used rhesus macaques to investigate an antibody-mediated reservoir targeting strategy, targeting the CD4 molecule rather than a viral protein, to deplete potential viral target cells irrespective of infection status. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not delayed in anti-CD4 treated animals compared with controls, likely due to the limited antibody-mediated cell depletion that occurred in rectal tissue and lymphoid follicles. Supported by ORIP (R24OD010976), NCI, and NIAID.
A Frog with Three Sex Chromosomes that Co-Mingle Together in Nature: Xenopus tropicalis Has a Degenerate W and a Y that Evolved from a Z Chromosome
Furman et al., PLOS Genetics. 2020.
https://pubmed.ncbi.nlm.nih.gov/33166278/
Genetic systems governing sexual differentiation vary among species. Furman et al. investigated a frog with three sex chromosomes, the Western clawed frog, Xenopus tropicalis. They demonstrate that natural populations from the western and eastern edges of Ghana have a young Y chromosome, and that a male-determining factor on this Y chromosome is in a similar genomic location as a previously known female-determining factor on the W chromosome. Their findings are consistent with theoretical expectations associated with recombination suppression on sex chromosomes and demonstrate that several characteristics of old and established sex chromosomes can arise well before they become cytogenetically distinguished. Supported by ORIP (P40OD010997) and NICHD.
Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation
Jelena et al., Nature Metabolism. 2020.
https://pubmed.ncbi.nlm.nih.gov/32839596
Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.
Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory
Lu et al., Frontiers in Genetics . 2020.
https://www.frontiersin.org/articles/10.3389/fgene.2020.562594/full
Xiphophorus interspecies hybrids represent a valuable model system to study heritable tumorigenesis. Although the ancestors of the two X. maculatus parental lines, Jp163 A and Jp163 B, were siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to a regulator encoded by the X. maculatus genome; the backcross hybrid progeny with X. hellerii or X. couchianus and Jp163 B exhibit melanoma on their flanks. Comparative genomic analyses revealed genetic differences are associated with pathways highlighting fundamental cellular functions. Disruption of these baselines may give rise to spontaneous or inducible tumorigenesis. Supported by ORIP (R24OD011120), NCI, and NIGMS.
Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model
Boas et al., PLOS One. 2020.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391
Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model for pancreatic cancer. H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. In summary, pancreatic cancer can be induced in a transgenic pig, and intra-arterial procedures using catheters designed for human interventions were feasible in this model. Supported by ORIP (U42OD011140) and NCI.