# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary/Abstract
 My major research interest is to understand molecular mechanisms of gene regulation and function in
the pathogenesis of cancer and cardiovascular disease, two major health burdens for our Veterans. We seek
to determine the fundamental molecular signals that regulate cellular function, and translate the findings in the
pathogenesis of disease using animal models, so as to identify novel molecular targets and strategies for
prevention and intervention of disease.
 Translational research on cancer pathogenesis and resistance to therapy. We have been
focused on the death receptor signaling pathways in regulating apoptosis of cancer cells and their roles in
cancer tumorigenesis and resistance to therapy. Our studies have demonstrated that modulating the Death-
Inducing Signaling Complex (DISC) determines the downstream survival and apoptosis signals. Recently, we
discovered a novel regulator, poly(ADP-ribose) polymerase 1 (PARP1), in the death receptor-5 DISC that
contribute to the resistance of pancreatic cancer to therapy, a critical hurdle for effective cancer treatment.
Based on this novel finding, our current VA merit review award (2014-2018) is to delineate the mechanisms
underlying DISC-associated PARP1 in regulating pancreatic cancer resistance to antibody immunotherapy with
a humanized anti-death receptor 5 antibody (TRA-8/CS1008). I will continue my long-term collaboration with
VA physician scientist, Jay M McDonald, MD (Pathology, Birmingham VA) and the inventor of TRA-8/CS1008,
Tong Zhou, MD (Medicine, UAB). As CS1008 therapy has been effective in clinical trials for some cancer but
resistant in others including pancreatic tumors, the overarching goal for our investigations is to elucidate the
molecular mechanisms and identify new compounds that sensitize pancreatic cancer to TRA-8-induced
apoptosis, thus overriding drug resistance and leading to successful therapies.
 Differentiation and reprogramming of vascular smooth muscle cells in vascular disease.
Phenotypic plasticity of vascular smooth muscle cells (VSMC) provides an excellent model to study the
function of cell differentiation in health and disease. We are particularly interested in studying how VSMC
become bone-like cells (vascular calcification). Using tissue-specific gene knockout mouse models, we have
demonstrated an essential role of the osteogenic transcription factor Runx2 in regulating vascular calcification,
a feature of atherosclerosis, diabetes and end stage renal disease. We have uncovered novel mechanisms
underlying Runx2 upregulation in the vasculature by increased oxidative stress and hyperglycemia. We have
also discovered a novel crosstalk between VSMC, macrophages and vascular stem cells in the development of
atherosclerotic calcification. We have published a body of work demonstrating a critical integrative role of
Runx2 upregulation in VSMC in promoting vascular pathology, which has been highly recognized and cited.
Our overarching goa...

## Key facts

- **NIH application ID:** 9814697
- **Project number:** 5IK6BX003617-04
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Yabing Chen
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814697

## Citation

> US National Institutes of Health, RePORTER application 9814697, BLR&D Research Career Scientist Award Application (5IK6BX003617-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9814697. Licensed CC0.

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