Job 63 - Assort Design

Request JD-000063 R&D

Audience: R&D • completed

Routing confidence: 95% • Candidates: R&D, Medical Affairs, Commercial

Routing reasons: ML fallback: low confidence (41% < 57%); The document discusses detailed genetic and molecular research findings related to nonalcoholic steatohepatitis (NASH), focusing on gene function, mouse models, and disease mechanisms, which align with research and development interests.; The content includes experimental methods, gene knockout mouse models, molecular biology mechanisms, and implications for developing treatments, which are typical for an R&D audience.; The document references scientific publications and funding agencies aligned with biomedical research, suggesting a primary audience of researchers and scientists rather than commercial or purely medical affairs professionals.

Why Routed Here

R And D at 45.5% ▼

ML predicted R And D at 45.5% confidence. Runner-up: Medical Affairs at 39.4%.

Top contributing terms (R And D)

Term	TF-IDF	Weight	Contribution
`mice`	0.0531	0.1035	0.0055
`gene`	0.0452	0.1086	0.0049
`the dna`	0.0513	0.0819	0.0042
`the mice`	0.0636	0.0634	0.004
`dna`	0.065	0.0552	0.0036
`the researchers`	0.0589	0.0564	0.0033
`understanding`	0.0274	0.1151	0.0032
`behind`	0.0244	0.1253	0.0031

Runner-up: Medical Affairs (39.4%)

Term	TF-IDF	Weight	Contribution
`fatty`	0.0445	0.0927	0.0041
`health`	0.0429	0.0878	0.0038
`news`	0.0417	0.0804	0.0034
`fatty liver`	0.0429	0.0718	0.0031
`why`	0.0358	0.0795	0.0028
`damage`	0.0579	0.046	0.0027
`cell`	0.0421	0.0587	0.0025
`cells`	0.045	0.0562	0.0025

All probabilities: Commercial: 15.1% · Medical Affairs: 39.4% · R And D: 45.5%

Source url

https://www.news-medical.net/news/20230209/Researchers-find-possible-genetic-basis-and-mouse-model-for-nonalcoholic-steatohepatitis.aspx

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Researchers find possible genetic basis and mouse model for nonalcoholic steatohepatitis Skip to content Menu Medical Home Life Sciences Home Become a Member Search Medical Home Life Sciences Home About Functional Food News Health A-Z Drugs Medical Devices Interviews White Papers More... MediKnowledge eBooks Posters Podcasts Newsletters Health & Personal Care Contact Meet the Team Advertise Search Become a Member Top Health Categories Coronavirus Disease COVID-19 Diet & Nutrition Artificial Intelligence Allergies Alzheimer's & Dementia Arthritis & Rheumatology Breast Cancer Breastfeeding Cold, Flu & Cough Dermatology Diabetes Eating Disorders Eye Health Gastrointestinal Health Heart Disease Lung Cancer Mental Health Parkinson's Disease Pregnancy Sleep Urology View Health A-Z × Top Health Categories Coronavirus Disease COVID-19 Eating Disorders Diet & Nutrition Eye Health Artificial Intelligence Gastrointestinal Health Allergies Heart Disease Alzheimer's & Dementia Lung Cancer Arthritis & Rheumatology Mental Health Breast Cancer Parkinson's Disease Breastfeeding Pregnancy Cold, Flu & Cough Sleep Dermatology Urology Diabetes View Health A-Z Medical Home Life Sciences Home About News Life Sciences A-Z White Papers Lab Equipment Interviews Newsletters Webinars More... eBooks Posters Podcasts Contact Meet the Team Advertise Search Become a Member White Papers MediKnowledge eBooks Posters Podcasts Newsletters Health & Personal Care Contact Meet the Team Advertise Search Become a Member Webinars eBooks Posters Podcasts Contact Meet the Team Advertise Search Become a Member Researchers find possible genetic basis and mouse model for nonalcoholic steatohepatitis Download PDF Copy Reviewed Reviewed by Emily Henderson, B.Sc. Feb 9 2023 A mutant or damaged gene may be a cause of a severe, mysterious form of nonalcoholic fatty liver disease, University of Illinois Urbana-Champaign researchers have found. Mice and human liver cells lacking the SRSF1 gene show all the hallmarks of nonalcoholic steatohepatitis, also known as NASH, the researchers found. The unique mouse model captures all three hallmarks of excess fat, inflammation and scarring in the liver, opening the doors to better understanding and development of treatments for NASH, said study leader Auinash Kalsotra, a biochemistry professor at Illinois. The researchers published their results in the journal Nature Communications . Nonalcoholic fatty liver disease affects an estimated 25% of Americans, according to the National Institutes of Health, and up to a third of patients will develop inflammation and scarring as well, falling under the NASH classification. "It's not really clear why certain people end up developing NASH," Kalsotra said. "So far, there haven't been any genes that have been directly linked to NASH. It's been thought of as a progression: After the liver is injured or it becomes fatty, if you don't check it, it's going to progress toward NASH. But not everybody with fatty liver develops NASH and it seems random who does, so it's very confusing as to why this happens." The other problem making NASH research difficult is the lack of good animal or cellular models for it, Kalsotra said. While some models incorporate one or two of the symptoms, and then other damage inflicted to mimic what is seen in NASH patients, they don't give an accurate portrayal of the disease. Kalsotra's group began studying SRSF1, a protein that assists in splicing RNA in the cell, to study its splicing activity. They bred a line of mice that were lacking the gene to learn about its splicing activity. The mice soon spontaneously developed all the symptoms of NASH. "We were very excited to see this, as we thought, this could be a model for the disease. But first, we had to figure out the mechanisms of why SRSF1 was connected to liver disease," said graduate student Waqar Arif, the first author of the study. The researchers found that the mechanism was not related to SRSF1's splicing activity, as first thought, but because it protected against DNA damage in the liver during the process of DNA unwinding so its code can be transcribed into RNA. Without the SRSF1 protein, liver cells began to shut down. "What happened was the cell wanted to die because of the extensive damage that was happening to the DNA. But it didn't have the energy for regular programmed cell death processes. The damage was so severe that everything just shut down," said Kalsotra, who also is affiliated with the Carl R. Woese Institute of Genomic Biology and the Cancer Center at Illinois. Related Stories Telehealth boosts uptake of genetic testing among adult survivors of childhood cancers Genetic variants in 11 regions of human genome influence the gut microbiome Do cocoa flavanols influence heart and fatty liver risk factors? It was the opposite of the pathway that had been assumed, Kalsotra said: Instead of excess fat leading to cell damage, the cell damage came first, and fat built up as a result of the cells not being able to perform their function of packaging up digested fats. Inflammation increased as the immune system tried to clear away dead and dying cells, and then fibrosis appeared as scars formed over patches of dead tissue to try to hold the liver together. The researchers saw this same sequence in both the mice without SRSF1 and in human liver cell lines depleted of SRSF1. "These findings tell us that the genome of the liver cells has to be properly maintained," Kalsotra said. "Liver cells are encountering toxins and DNA damage more than any other cells in our body. This study illustrates that when liver cells encounter excessive DNA damage, these NASH symptoms develop. SRSF1 plays a protective role against that. It acts as a guardian of the liver genome." The researchers hope the mice will aid other researchers studying NASH, both in terms of understanding the disease and in exploring potential treatment targets. "We want to see whether there are certain conditions where SRSF1 has been inactivated in some way in human livers or other animals," Kalsotra said. "Maybe there are some toxins or medicines or other environmental pollutants, for example, that could cause inactivation of the SRSF1 gene. Figuring out the triggers that cause silencing of SRSF1 could point to treatment targets, and whether things like anticancer drugs that prevent DNA damage could be applied here. It's interesting to note that many NASH patients develop cancer as well. Is that linked to the DNA damage?" The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well. The National Institutes of Health, the Cancer Center at Illinois, the American Cancer Society and the National Science Foundation supported this work. Source: University of Illinois at Urbana-Champaign Journal reference: DOI: 10.1038/s41467-023-35932-3 Posted in: Medical Research News | Medical Condition News Comments (0) Download PDF Copy Suggested Reading Type 2 diabetes and hypertension share a genetic link, study shows SynGenSys introduces Liver.SET synthetic promoter library for liver-specific gene expression for in vivo gene therapies Polygenic analysis provides new insight into hypermobile Ehlers–Danlos syndrome Cornell study finds existing drug could boost liver cancer immunotherapy Study reveals how inherited genetic abnormalities raise Barrett’s esophagus risk Obesity drives shared genetic risk behind many chronic disease combinations Study explores whether a bidirectional causal link exists between MASLD and sarcopenia Liver-derived protein supports bone health in males Comments The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical. 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Researchers identified the SRSF1 gene as a protective factor against DNA damage in liver cells, and its absence in a novel mouse model replicates all hallmarks of nonalcoholic steatohepatitis (NASH), proposing a new genetic basis for the disease.

5 bullets 3 citations (0 strong) 7 tags 6 clues 1 high-risk flag

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Decision Bullets

Technical Summary: Validate the causative link between SRSF1 loss and NASH by assessing DNA damage and downstream pathology in diverse models.

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" The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well.

…applied here. It's interesting to note that many NASH patients develop cancer as well. Is that linked to the DNA damage? " The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well. The National Institutes of Health, the Cancer Center at Illinois, the American Cancer Society and the National Science …

Offsets: 6512–6665

Confidence: 75% Medium
Assumptions: SRSF1 inactivation is a primary driver of NASH pathology, not a secondary consequence; the mouse model reflects human disease mechanisms accurately.

View citation support (1)

The unique mouse model captures all three hallmarks of excess fat, inflammation and scarring in the liver, opening the doors to better understanding and development of treatments for NASH, said study leader Auinash Kalsotra, a biochemistry professor at Illinois.

…acking the SRSF1 gene show all the hallmarks of nonalcoholic steatohepatitis, also known as NASH, the researchers found. The unique mouse model captures all three hallmarks of excess fat, inflammation and scarring in the liver, opening the doors to better understanding and development of treatments for NASH, said study leader Auinash Kalsotra, a biochemistry professor at Illinois . The researchers published their results in the journal Nature Communications . Nonalcoholic fatty liver disease affect…

Offsets: 2073–2335

Confidence: 69% Medium
Key Risks: Model may not fully capture human NASH heterogeneity; unknown confounders affecting SRSF1 function; translational relevance of SRSF1-targeted interventions is uncertain.

View citation support (1)

No supporting quote found.

Confidence: 20% Weak
Experimental Plan: Conduct longitudinal studies in mice and human hepatocyte cultures with controlled SRSF1 knockdown; test environmental/toxic triggers affecting SRSF1; assess DNA damage markers, inflammation, fibrosis progression, and reversibility with DNA-protective agents.

View citation support (1)

No supporting quote found.

Confidence: 20% Weak
Next Steps: Screen NASH patient liver samples for SRSF1 expression and DNA damage profiles; explore other DNA-protective genes as candidates; develop targeted therapies mitigating DNA damage-induced liver pathology.

View citation support (1)

" The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well.

…applied here. It's interesting to note that many NASH patients develop cancer as well. Is that linked to the DNA damage? " The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well. The National Institutes of Health, the Cancer Center at Illinois, the American Cancer Society and the National Science …

Offsets: 6512–6665

Confidence: 75% Medium

Mind Map

mindmap
  root((NASH Genetic Basis & Model))
    SRSF1 Gene
      Protective role against DNA damage
      Independent of RNA splicing
    Mouse Model
      Lacking SRSF1
      Exhibits steatosis, inflammation, fibrosis
    Mechanism
      DNA damage precedes fat accumulation
      Cell shutdown & death pathway
    Human Relevance
      Similar effects in liver cell lines
      Potential environmental/toxic triggers
    Research Directions
      Validate causality and mechanistic details
      Explore other genome maintenance genes
      Therapeutic target identification
      Patient sample screening

#	Bullet	Supporting Quote	Level
1	Technical Summary: Validate the causative link between SRSF1 loss and NASH by assessing DNA damage and downstream pathology in diverse models.	"" The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well."	Medium
2	Assumptions: SRSF1 inactivation is a primary driver of NASH pathology, not a secondary consequence; the mouse model reflects human disease mechanisms accurately.	"The unique mouse model captures all three hallmarks of excess fat, inflammation and scarring in the liver, opening the doors to better understanding and development of treatments for NASH, said study leader Auinash Kalsotra, a biochemistry professor at Illinois."	Medium
3	Key Risks: Model may not fully capture human NASH heterogeneity; unknown confounders affecting SRSF1 function; translational relevance of SRSF1-targeted interventions is uncertain.	—	None
4	Experimental Plan: Conduct longitudinal studies in mice and human hepatocyte cultures with controlled SRSF1 knockdown; test environmental/toxic triggers affecting SRSF1; assess DNA damage markers, inflammation, fibrosis progression, and reversibility with DNA-protective agents.	—	None
5	Next Steps: Screen NASH patient liver samples for SRSF1 expression and DNA damage profiles; explore other DNA-protective genes as candidates; develop targeted therapies mitigating DNA damage-induced liver pathology.	"" The researchers also plan to explore whether other genes protect DNA in this way, and whether damage to any of them could cause NASH pathology as well."	Medium

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Researchers identified the SRSF1 gene as a protective factor against DNA damage in liver cells, and its absence in a novel mouse model replicates all hallmarks of nonalcoholic steatohepatitis (NASH),

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