Selected Grantee Publications
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- 15 results found
- Cancer
- Cardiovascular
- 2021
An NR2F1-Specific Agonist Suppresses Metastasis by Inducing Cancer Cell Dormancy
Khalil et al., The Journal of Experimental Medicine. 2021.
Researchers described the discovery of a nuclear receptor NR2F1 antagonist that specifically activates dormancy programs in malignant cells. Agonist treatment resulted in a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest in multiple human cell lines, as well as patient-derived organoids. This effect was lost when NR2F1 was knocked out. In mice, agonist treatment resulted in inhibition of lung metastasis of head and neck squamous cell carcinomas, even after cessation of the treatment. This work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis. Supported by ORIP (S10OD018522 and S10OD026880) and others.
Negative Inotropic Mechanisms of β-cardiotoxin in Cardiomyocytes by Depression of Myofilament ATPase Activity without Activation of the Classical β-Adrenergic Pathway
Lertwanakarn et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-00282-x
Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy. Supported by ORIP (P40OD010960) and NHLBI.
MIC-Drop: A Platform for Large-scale In Vivo CRISPR Screens
Parvez et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/34413171/
CRISPR screens in animals are challenging because generating, validating, and keeping track of large numbers of mutant animals is prohibitive. These authors introduce Multiplexed Intermixed CRISPR Droplets (MIC-Drop), a platform combining droplet microfluidics, single-needle en masse CRISPR ribonucleoprotein injections, and DNA barcoding to enable large-scale functional genetic screens in zebrafish. In one application, they showed that MIC-Drop could identify small-molecule targets. Furthermore, in a MIC-Drop screen of 188 poorly characterized genes, they discovered several genes important for cardiac development and function. With the potential to scale to thousands of genes, MIC-Drop enables genome-scale reverse genetic screens in model organisms. Supported by ORIP (R24OD017870), NIGMS, and NHLBI.
Effects of Early Daily Alcohol Exposure on Placental Function and Fetal Growth in a Rhesus Macaque Model
Lo et al., American Journal of Obstetrics and Gynecology. 2021.
https://www.sciencedirect.com/science/article/pii/S0002937821008309?via%3Dihub=
In a rhesus macaque model for chronic prenatal alcohol exposure, daily consumption during early pregnancy significantly diminished placental perfusion at mid to late gestation and significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy. These findings were associated with the presence of microscopic placental infarctions. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury that persisted throughout pregnancy. Supported by ORIP (P51OD011092), NICHD, and NIAAA.
Sexual Dimorphic Impact of Adult-Onset Somatopause on Life Span and Age-Induced Osteoarthritis
Poudel et al., Aging Cell. 2021.
https://pubmed.ncbi.nlm.nih.gov/?term=Poudel%20SB&cauthor_id=34240807
Osteoarthritis (OA) is a major cause of disability worldwide. In humans, the age-associated decline in growth hormone (GH) levels was hypothesized to play a role in the etiology of OA. Investigators studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity in aged mice. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice. In conclusion, while their life span increased, AOiGHD female mice’s health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity. Supported by ORIP (S10OD010751) and others.
Deep Learning-Based Framework for Cardiac Function Assessment in Embryonic Zebrafish from Heart Beating Videos
Naderi et al., Computers in Biology and Medicine. 2021.
https://www.sciencedirect.com/science/article/pii/S0010482521003590
Zebrafish is a powerful model system for a host of biological investigations, cardiovascular studies, and genetic screening. However, the current methods for quantifying and monitoring zebrafish cardiac functions involve tedious manual work and inconsistent estimations. Naderi et al. developed a Zebrafish Automatic Cardiovascular Assessment Framework (ZACAF) based on a U-net deep learning model for automated assessment of cardiovascular indices, such as ejection fraction (EF) and fractional shortening (FS) from microscopic videos of wildtype and cardiomyopathy mutant zebrafish embryos. The framework could be widely applicable with any laboratory resources, and the automatic feature holds promise to enable efficient, consistent, and reliable processing and analysis capacity. Supported by ORIP (R44OD024874)
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.
Phase Separation Drives Aberrant Chromatin Looping and Cancer Development
Ahn et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03662-5
How unstructured intrinsically disordered regions (IDRs) contribute to oncogenesis is elusive. Using an Orbitrap fusion tribrid mass spectrometer, investigators show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias, are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad “super-enhancer”-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. This report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumor transformation. Supported by ORIP (S10OD018445).
Single-Cell Protein Activity Analysis Identifies Recurrence-Associated Renal Tumor Macrophages
Obradovic et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.04.038
Post-surgery course of clear cell renal carcinoma (ccRCC) is mixed because of the heterogeneity of the disease. Using high-performance computing cluster and storage systems, investigators established an inclusive ccRCC tumor microenvironment (TME) map by using single-cell RNA sequencing data of subpopulations of tumor and tumor-adjacent tissues. Analysis of the data identified key TME subpopulations as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant cell populations. Specifically, the study uncovered a tumor-specific macrophage subpopulation, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, markers of this subpopulation were significantly enriched in tumors from patients who recurred following surgery. Supported by ORIP (S10OD012351, S10OD021764) and others.
Mineralocorticoid Receptor Blockade Normalizes Coronary Resistance in Obese Swine Independent of Functional Alterations in Kv Channels
Goodwill et al., Basic Research in Cardiology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34018061/
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening. Supported by ORIP (U42OD011140, S10OD023438), NHLBI, and NIBIB.