# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2023 · —

## Abstract

Pancreatitis is a potentially fatal disease of exocrine pancreas, with significant morbidity and
mortality, and a heavy burden on the US healthcare system. The disease is common in Veterans
patient population. Its mechanism remains obscure, and no specific or effective treatment is
available. Pancreatitis is not only associated with poor quality of life but is also a major risk factor
for the deadly pancreatic cancer. The pancreatic acinar cell is a major participant in both acute
and chronic pancreatitis. Its’ central physiologic function is to synthesize, transport, and secrete
digestive enzymes. This is accomplished through coordinated actions of mitochondria, which
provide energy (ATP); lysosomes and autophagy, mediating removal of damaged or dysfunctional
organelles; and the endoplasmic reticulum (ER), a site of enzyme synthesis and folding.
 Several years ago we put forward a novel concept that Dysfunction of the pancreatic acinar
cell organellar machinery mediating protein processing, trafficking, and degradation is
central to the pathogenesis of acute pancreatitis. Our studies (as well as by other groups)
have validated this hypothesis. These studies have been mostly performed within the framework
of an NIH/NIDDK Program Project on which I serve as PD/PI – the first ever Program grant on
pancreatitis, integrating the work of leading pancreatologists from 5 institutions across the US.
We showed that both experimental and human pancreatitis are associated with profound
disordering of acinar cell lysosomal, autophagy and mitochondrial pathways, and characterized
the underlying mechanisms. We further showed that genetic and pharmacologic modulations of
these pathways can ameliorate (or, conversely, cause) the disease.
 My current research provides further insight into these mechanisms. Studies supported by VA
Merit award investigate the role of autophagy in chronic pancreatitis by using a novel, clinically
relevant mouse model with pancreas-specific genetic insufficiency of the protein SPINK1
(mutations in which increase the risk of chronic pancreatitis in humans 20- to 40-fold). Studies
supported by NIH/NIAAA and DOD investigate the role of organelle disorders in pancreatitis
induced by environmental factors. The NIAAA-funded project examines the role of impaired
lysosomal/autophagy pathway in the inflammatory response of alcoholic pancreatitis, and
proposes new pharmacologic approaches. The DOD-funded project investigates the role of
mitochondrial permeability transition pore (MPTP) in pancreatitis induced by combined action of
alcohol and smoking, and analyzes the interrelations between mitochondrial dysfunction and ER
stress. We apply pharmacologic and genetic approaches to examine beneficial effects of MPTP
blockade in models of pancreatitis caused by alcohol and cigarette smoke. The focus of my most
recent studies is on elucidating the mechanisms linking organellar disfunction to pancreatitis
pathologies such as inflammation and cell de...

## Key facts

- **NIH application ID:** 10512760
- **Project number:** 5IK6BX005793-02
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** ANNA S. GUKOVSKAYA
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512760

## Citation

> US National Institutes of Health, RePORTER application 10512760, BLRD Research Career Scientist Award Application (5IK6BX005793-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10512760. Licensed CC0.

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