# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · JESSE BROWN VA MEDICAL CENTER · 2021 · —

## Abstract

The overarching theme of my current research is to understand how growth hormone (GH) and insulin-like
growth factor I (IGF1) regulate adult metabolic function and how dysregulation of GH/IGF1 production and
signaling contributes to the progression of metabolic disease, as well as related tissue injury and repair. A major
focus of my work is to understand the etiology of non-alcoholic fatty liver disease (NAFLD). NAFLD represents
a spectrum of excess fat accumulation in the liver (steatosis) without or with inflammation/fibrosis (non-alcoholic
steatohepatitis - NASH). NAFLD is commonly observed in obesity and type 2 diabetes, but is also observed in
non-obese patients associated with cardiovascular disease, where all diseases are more prevalent in Veterans,
compared to the general population. NASH increases the risk of developing liver cancer, and is now recognized
as the leading cause for liver transplantation. Dietary fatty acids (FA) and FA derived from adipose tissue
lipolysis, due to systemic insulin resistance, are major contributors to NAFLD. In addition, enhanced hepatic de
novo lipogenesis (DNL) contributes to NAFLD. Clinical and experimental studies show NAFLD is associated with
reduced GH-signaling (reflected by low plasma GH and hepatic GH resistance, leading to low IGF1 levels). The
reduction in GH-signaling may exacerbate NAFLD, based on studies showing SNPs within the GH / GH receptor
(GHR) /JAK2 / Stat5 signaling pathway are associated with NAFLD. Also, increasing GH can reduce NAFLD in
both humans and mice.
 We have reported that adult-onset loss of hepatocyte GH signaling (aHepGHRkd; GHRfl/fl mice treated with an
adeno-associated viral vector expressing thyroxine binding globulin promoter driven Cre [AAV8-TBGp-Cre]) led
to the rapid development of steatosis, associated with an increase in DNL (Cordoba-Chacon et al., Diabetes
2015). Of translational relevance, hepatic DNL/steatosis after aHepGHRkd is sustained with age and associated
with hepatocyte ballooning, inflammation and fibrosis (hallmarks of NASH; Cordoba-Chacon et al.,
Endocrinology 2018). Studies outlined in my current R01 take a multi-level approach to define the
biochemical/molecular mechanisms by which hepatocyte GH-signaling directly controls glycolysis-driven DNL
and steatosis, by manipulating hepatocyte GH signaling in mice by hepatocyte-specific, AAV-vector delivery of
transgenes within the GH-signaling pathway then assessing; gene and protein expression of enzymes in
glycolytic and lipogenic pathways, fatty acid composition by GC/MS, glycolytic flux and TCA cycle intermediates
under hyperinsulinemic:hyperglycemic clamps, using stable isotope tracers. Studies outlined in my current
BL&RD VA Merit are focused how the reduction in hepatocyte GH signaling contributes to diet-induced NASH
and how reconstitution of the GHR signaling pathway (specifically Stat5b activity and/or IGF1 using AAV vector
delivery) may prevent and/or reverse steatosis and liver injury. To d...

## Key facts

- **NIH application ID:** 10103993
- **Project number:** 1IK6BX005382-01
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Rhonda D Kineman
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103993

## Citation

> US National Institutes of Health, RePORTER application 10103993, BLRD Research Career Scientist Award Application (1IK6BX005382-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10103993. Licensed CC0.

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