# Optogenetic stimulation of TMEM16F to control phospholipid flip-flop

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $193,765

## Abstract

SUMMARY
Phospholipid flip-flop on cell membranes can exert profound impacts on cellular signaling and
functions, including apoptosis, phagocytosis, blood coagulation, membrane vesicle shedding,
bone mineralization, cell-cell fusion, fertilization, viral infection including HIV and SARS-CoV2
infections. Nevertheless, how phospholipid flip-flop leads to the observed cellular responses is
largely elusive. The recent identifications of phospholipid scramblases and flippases have
enabled genetic manipulations of these critical phospholipid transporters, which greatly advanced
our understanding on the biology of phospholipid flip-flop. However, phospholipid flip-flop is a
dynamic process and the genetic manipulations only allow us to observe the end results, which
hinders gaining mechanistic understanding phospholipid flip-flop in various physiological process
in real time. In this application, we aim to test the feasibility of developing a genetically encoded,
optogenetic toolbox to precisely control phospholipid flip-flop with light at high temporal and spatial
resolution and in real time. Our proposal is based on our extensive experience on the recently
discovered calcium-activated phospholipid scramblase (CaPLSase) TMEM16F at molecular and
cellular levels. In response to intracellular calcium increase, TMEM16F can rapidly catalyze
phospholipid flip-flop, efficiently disrupt membrane environment and trigger wide spectrum of
cellular changes. Here, we will use two complementary but independent approaches to develop
the optogenetic tools to control phospholipid flip-flop. First, we will coexpress various calcium-
mobilizing optogenetic tools to indirectly activate TMEM16F utilizing its calcium sensing property.
Second, we will engineer light sensing motifs into TMEM16F to enable direct light control of its
activities. If successful, the optogenetic toolbox developed in this high-risk, high-reward
application will have profound impacts and broad applications in membrane biology, cell biology,
physiology, hematology, immunology, virology and medicine.

## Key facts

- **NIH application ID:** 10433070
- **Project number:** 1R21GM146152-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Huanghe Yang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,765
- **Award type:** 1
- **Project period:** 2022-04-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433070

## Citation

> US National Institutes of Health, RePORTER application 10433070, Optogenetic stimulation of TMEM16F to control phospholipid flip-flop (1R21GM146152-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10433070. Licensed CC0.

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