Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Treating cardiovascular disorders -- and more -- with the flips of a switch

27.04.2018

Using light to switch calcium ions on and off may have implications for regenerative medicine

You've heard of "nature versus nurture," and philosophers argue about which is more important. But how does this work on the cellular level?


Cardiovascular disease treatment.

Credit: Yubin Zhou, Texas A&M University Health Science Center

Although genes stay the same throughout the lifespan, genetic code isn't necessarily a person's destiny. In fact, genes can be switched on and off to regulate a number of activities within cells. The body does this naturally in response to internal needs or changes in the external environment, and now scientists are able to switch these processes on and off in the lab.

In other words, researchers have created tools that would enable real-time activation of target genes in specific locations in the genome. This technology may help scientists to illuminate the gene function during different biological processes and hopefully be useful in regenerative medicine. Researchers at Texas A&M are creating a system to do this using two common elements: calcium and light.

Calcium--capable of far more than building strong bones--plays an important role in this system, as its signals regulate a number of activities within the cell, from growth and metabolism to homeostasis.

Turning on the flow of calcium ions

Yubin Zhou, PhD, associate professor at the Texas A&M Institute of Biosciences and Technology, leads the study developing what he calls the CaRROT system (for calcium-responsive transcriptional reprogramming tool). This system can control the transcription of genes within the body with high precision--in other words, it can dictate how, when and where genes create proteins that perform various cellular functions.

CaRROT uses a simple pulse of light or chemicals that can induce the flow of calcium ions into cells. The researchers described their technique in a recent article published in the journal ACS Synthetic Biology. "This technology should allow scientists to turn on or off a diverse array of genes at any location by simply switching the light or adding or withdrawing activating compounds," Zhou said.

The researchers designed CaRROT to hijack the calcium signals generated by light (with Opto-CRAC, another technology Zhou and his team developed) to deliver the genome-engineering tool derived from the CRISPR/Cas9 system to turn on genes. "When the light is switched on, the gates controlling calcium ions open to allow the flow of calcium from the external space into the cytoplasm of the cell," said Nhung Nguyen, a graduate student in Zhou's lab who led this work. "This process ultimately turns on the expression of specific genes." The turning on of gene expression then leads to changes in the function of the cell.

"We have screened dozens of engineered proteins and undergone numerous rounds of optimization to make the CaRROT system strictly responsive to light," added Lian He, PhD, a graduate student in Zhou's lab and a co-first author of the study. To evaluate how effective CaRROT really is in mammalian cells, the team will test it on genes that control the differentiation of neuron and skeletal muscle. They hope that they can use CaRROT in regenerative medicine to drive the precise differentiation of stem cells into whatever type of organ is required, just by illuminating the cells with light.

"The improvement of light penetration in deep tissue gives us the optimism that we could use CaRROT to reprogram cells in damaged organs," said Yun Huang, PhD, a collaborative senior author of the study. "It is possible that one day, by just exposing the tissues to light, we can heal the wound or accelerate the regeneration of injured tissues by photo-tuning coordinated gene expression."

Turning calcium influx off

In a second study recently published in the journal Angewandte Chemie as a cover story, Zhou and his team invented a new optogenetic tool that can do the opposite trick. With light shining upon cells in the 'excitable' tissues such as the nervous and cardiovascular systems, calcium influx through gateways on the membrane of the cell, called voltage-gated calcium channels, can be turned off. These channels, which constitute the major route of calcium entry into the cell, regulate a series of physiological processes. Because their dysfunction is involved in many diseases, they are considered an important therapeutic target for cardiovascular and neuropsychiatric disorders.

Traditional calcium-channel blockers approved by the United States Food and Drug Administration have been widely used to treat cardiovascular disorders including high blood pressure, arrhythmia and coronary artery disease. However, these drugs tend to cause side effects--including headache, edema, dangerously low blood pressure and palpitations--due to their cytotoxicity and off-target effects. "Because of these side effects, generating new interventional approaches to complement the traditional calcium-channel blockers is much needed in the clinic," Zhou said. "Our new optogenetic tool provides a non-conventional method to interrogate physiological and pathophysiological processes medicated by these voltage-gated calcium channels."

Zhou and his collaborators combined genetic strategies with optical techniques to engineer a novel class of genetically encoded inhibitors for these voltage-gated calcium channels. "After tremendous efforts of optimization, we developed an ideal photoswitchable inhibitor, which we're calling optoRGK. OptoRGK exhibited excellent light-inducible inhibition of calcium ion entry in excitable cells," said Guolin Ma, PhD, an assistant project scientist in Zhou's lab, who spearheaded the project.

The team tested this tool in cardiac muscle cells, which showed rhythmic oscillations of calcium in the dark that matched the heart beating rhythm. "However, upon blue light illumination, the rhythmic oscillations can be substantially reduced or even terminated," Zhou said. "Notably, this process is totally reversible after removal of the light source."

With this method, researchers can regulate the activity of excitable cells in the nervous and cardiovascular systems. "Complementary to the photoactivatable Opto-CRAC system, the optoRGK toolkit provides a unique opportunity to switch off calcium signals in excitable cells," said Youjun Wang, PhD, a collaborator of this study from Beijing Normal University.

"Our novel optogenetic tools can be conveniently applied to control a wide range of physiological processes mediated by voltage-gated calcium channels in multiple biological systems," Zhou added. "While traditional voltage-gated calcium channel blockers lack reversibility, selectivity and tissue-specificity, optoRGK opens exciting opportunities to intervene in related physiological processes with unprecedented precision. We hope that these kinds of studies will eventually lead to new generation of optogenetic devices for curing cancer, cardiovascular and neurological diseases."

Media Contact

Tamim Choudhury
tchoudhury@tamhsc.edu
979-436-0619

http://www.tamu.edu 

Tamim Choudhury | EurekAlert!
Further information:
https://vitalrecord.tamhsc.edu/treating-cardiovascular-disorders-and-more-with-the-flip-of-a-switch/

More articles from Health and Medicine:

nachricht Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Machine-learning predicted a superhard and high-energy-density tungsten nitride

18.07.2018 | Materials Sciences

NYSCF researchers develop novel bioengineering technique for personalized bone grafts

18.07.2018 | Life Sciences

Why might reading make myopic?

18.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>