# Calcium/ Calmodulin Activated Kinases in Smooth Muscle

> **NIH NIH R56** · ALBANY MEDICAL COLLEGE · 2022 · $582,904

## Abstract

Project Summary: This ongoing research project is aimed at defining functions of multi-functional
serine/threonine Ca2+/Calmodulin-dependent protein kinase II (CaMKII) isozymes in injury- and disease-
induced vascular remodeling. CaMKII is structurally complex and is expressed as a large hetero-multimeric
holoenzyme with 12-14 individual kinase subunits. CAMK2 genes undergo extensive alternative splicing to
produce variants that can affect holoenzyme subcellular localization and protein interactions. The central
hypothesis is that cell-specific expression and activation of CaMKII isoforms and splice variants are functional
determinants of integrated vascular remodeling in response to injury and disease.
The first specific aim extends our expertise in CaMKII structure and function in vascular smooth muscle to the
vascular endothelium, in the context of an in vivo mouse model of intraluminal arterial injury that simulates
aspects of in-stent restenosis. The functions of vascular endothelial cell CaMKII isoforms in re-
endothelialization following intraluminal injury are tested by conditional knockout of specific Camk2 genes in
genetically engineered mice. Regulation of the CaMKII isoform by STAT3 and the role of CaMKII in
mediating STAT3-dependent functions are tested in this inflammatory environment. The second specific aim
capitalizes on knowledge of CaMKII variant expression in vascular smooth muscle and tests the functional
significance of an alternatively spliced c-terminal amino acid sequence in CaMKIIthat mediates formation of a
CaMKII/Fyn complex, and subsequent regulation of cellular processes involved in vascular smooth muscle
cell motility and proliferation A novel CaMKII antisense exon-skipping oligonucleotide (ESO) approach,
designed to precisely interfere with expression of this sequence has been validated in vitro. ESOs will be
administered to mice prior to intraluminal arterial injury with the goal of limiting vascular smooth muscle
migration to the intima and subsequent neointimal hyperplasia, without affecting vasculoprotective endothelial
regeneration. The final aim investigates the function of CaMKII isoforms in promoting programmed cell death
by necroptosis in vascular smooth muscle and the role of this mechanism is promoting progression of
abdominal aortic aneurysm. This aim is carried out in collaboration with labs at Augusta University and the
University of Wisconsin and is investigated using mouse models of aortic aneurysm and conditional knockout
of specific Camk2 genes in vascular smooth muscle.
Relevance: Accomplishing these aims will provide detailed information on the functional importance of specific
CaMKII isoform variants in vascular injury, in stent-restenosis and aneurysmal disease. Application of
antisense ESOs targeting CaMKII may provide novel therapeutic approaches to mitigate progression of
vascular disease.

## Key facts

- **NIH application ID:** 10705334
- **Project number:** 2R56HL049426-25A1
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** HAROLD A SINGER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $582,904
- **Award type:** 2
- **Project period:** 1994-07-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705334

## Citation

> US National Institutes of Health, RePORTER application 10705334, Calcium/ Calmodulin Activated Kinases in Smooth Muscle (2R56HL049426-25A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705334. Licensed CC0.

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