# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

The morbidity and mortality associated with obesity is a major health problem in the VA patient
population. There is abundant evidence that obesity confers increased risk for various forms of cancer. The
VA reports ~40,000 new cases of cancer per year and ~2.7-3% are liver cancer. Obesity is associated with
metabolic disturbances such as non-alcoholic fatty liver disease (NAFLD) and its more severe form non-
alcoholic steatosis (NASH) and these are risk factors for both cirrhosis and liver cancer. So chronic liver
disease, whether induced by viral infection, alcohol use, obesity or any combination thereof, is the major risk
factor for cirrhosis and ultimately liver cancer. The Veteran population is at high risk for obesity-associated liver
disease and hence liver cancer so it is important to understand the etiology and pathogenesis of the disease.
Similarly the incidence of breast cancer is increased in obese populations, and the epidemiologic evidence for
the obesity-breast cancer connection is particularly strong in post-menopausal women. One in eight women
will be diagnosed with breast cancer during their lifetime. As increasing numbers of women enter military
service, women’s health issues become a greater concern for the VA. Battlefield exposures to toxicants and
bad nutrition may trigger the metabolic syndrome that is associated with higher risk of heart disease, diabetes
and cancer. Studies to understand how environmental and nutritional events impact the regulation of normal
metabolism will shed greater light on how metabolic dysregulation increases the risk of various diseases.
 We have found that reducing inflammation and insulin resistance reduces breast cancer growth in mice.
This can be done by providing high levels of omega3 fatty acids or through a nutritional intervention involving
time-restricted feeding of a high-fat diet. Due to the link between obesity, insulin resistance and breast cancer
risk in post-menopausal women, and the potential that a similar time-restricted, dietary intervention could
protect against breast cancer in humans, it is important to understand how correcting insulin resistance
reduces the risk of breast cancer growth in mice and investigate the physiological changes that may drive
tumor growth in obesity.
 We have published that loss of a particular RNA splicing factor SRSF3 in hepatocytes causes chronic
liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer.
So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar
to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both
humans and mice, in addition to being lost in liver cancer, so loss of SRSF3 may be the precipitating event that
triggers progressive liver disease. Our studies will address key questions concerning the fundamental
biological process of protein homeostasis and carcinogenesis in t...

## Key facts

- **NIH application ID:** 10219156
- **Project number:** 5IK6BX005224-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** NICHOLAS J WEBSTER
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219156

## Citation

> US National Institutes of Health, RePORTER application 10219156, BLR&D Research Career Scientist Award Application (5IK6BX005224-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219156. Licensed CC0.

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