期刊
CELL STEM CELL
卷 27, 期 6, 页码 876-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2020.11.009
关键词
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资金
- UCSF Program for Breakthrough Biomedical Research
- Sandler Foundation
- UCSF QBI Coronavirus Research Group (QCRG)
- NIH [DP2NS116769, F32GM133118, U19 AI077439, R35 HL145235, 5DP1DA038043]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK121169]
- Larry L. Hillblom Foundation
- National Institutes of Health's NHLBI [1F30HL149180-01]
- National Institutes of Health's Medical Scientist Training Program at the Yale School of Medicine
- DoD PRCRP Horizon Award [DoD: W81XWH-19-1-0594]
- Program for Breakthrough Biomedical Research at UCSF
- Sandler Foundation at UCSF
- National Cancer Institute [R01 CA240984]
- National Institute of General Medical Sciences [R01 GM123977]
- LGR-ERA Award
- Massachusetts General Hospital
- National Heart, Lung, and Blood Institute [R01HL1427, R01HL148565, R01HL148050]
- Fondation Leducq [TNE-18CVD04]
SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.
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