# Structural Dynamics of Cardiac Muscle Calcium ATPase Regulation

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $782,326

## Abstract

Project Summary/Abstract
To create a roadmap for rational therapeutic design targeting Ca dysregulation, associated with heart failure
and arrhythmia, we seek to understand the protein interactions and structural dynamics that regulate active Ca
transport in cardiac muscle. Previous work focused on two membrane proteins, the sarcoplasmic reticulum
(SR) Ca-ATPase (SERCA), in both skeletal and cardiac muscle, and its principal cardiac peptide subunit
regulator: phospholamban (PLB). The project now focuses on the heart (SERCA2a isoform) and extends to
additional peptide regulators. Our core technology is site-directed spectroscopy, in both purified proteins
and living cells. We develop and apply innovative and complementary methods in site-directed labeling,
fluorescence, EPR, and crystallography, with results integrated by computational simulations and function
in biochemical and cellular assays. Aims 1&2 identify fundamental mechanisms, while Aim 3 combines
these techniques and resultant insights to develop biophysical assays for therapeutic design. Aim 1
focuses on the functional dynamics of SERCA2a and its key structural transitions that mediate catalytic
mechanism, focusing on steps that are critical for regulation in the heart. Added emphasis is now placed on
detection of transient structural kinetics, using stopped-flow FRET methods pioneered by our lab, to directly
relate SERCA structure and function. Aim 2 investigates mechanisms by which SERCA is regulated by three
cardiac peptide subunits: PLB, sarcolipin (SLN), and DWORF. Aim 3 employs the insights of Aims 1&2 and
our breakthroughs in high-throughput fluorescence detection, to implement novel small-molecule screening
assays, with the ultimate goal of therapeutic discovery for heart disease. New compounds identified in Aim 3
feed back to provide mechanistic insight in Aims 1&2. Thus our Aims are synergistic, strengthening each
other with new insights and hypotheses, yet not interdependent, since feasibility has been established
independently for each Aim and sub-Aim. This project brings together a powerful and complementary
combination of techniques and concepts, from biophysics to chemical biology to molecular genetics to cell
biology, performed by a highly-integrated collaborative team, now adding a subcontract (Zima) to further
enhance cellular and physiological relevance. The project remains grounded in fundamental biophysical
mechanisms, and continues to exploit the recognized value of SERCA Ca pumps as therapeutic targets for
major unmet needs in public health, targeting not only the heart, but also skeletal muscle (muscular
dystrophy, sarcopenia), neurodegeneration (Alzheimer’s, Parkinson’s), and metabolic disease (diabetes,
obesity). Thus, the significance of our work extends well beyond the heart. Our biophysical approaches
will surely play a crucial role in understanding SERCA regulation, and also in controlling these functions.
Our collaborators and consultants include scientis...

## Key facts

- **NIH application ID:** 9981062
- **Project number:** 9R01HL139065-36A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** RAZVAN LIVIU CORNEA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $782,326
- **Award type:** 9
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981062

## Citation

> US National Institutes of Health, RePORTER application 9981062, Structural Dynamics of Cardiac Muscle Calcium ATPase Regulation (9R01HL139065-36A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9981062. Licensed CC0.

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