Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

JAK2 enzyme helps protect brain cells, wreaks havoc on blood vessels

27.10.2003


How the same enzyme helps protect brain cells from the destruction of Alzheimer’s yet contributes to the blood vessel disease of diabetics is a puzzle Dr. Mario B. Marrero wants to solve.


Dr. Mario B. Marrero is studying an enzyme that helps protect brain cells from destruction but wreaks havoc on the blood vessels of diabetics.



"I call JAK2 the good, the bad and the ugly because its function depends on the cell type and where it acts," says the biochemist at the Medical College of Georgia who wants to eliminate – or at least control – the "bad" and "ugly."

JAK2, or janus kinase 2, is an enzyme found in all cells that plays an important role in development and growth; mice lacking this enzyme die in utero, Dr. Marrero says. After birth, the enzyme becomes a two-edged sword that activates or deactivates other proteins and plays a role in Alzheimer’s, diabetes, hypertension and kidney failure.


When JAK2 is good, it helps protect brain cells from Alzheimer’s disease by blocking the action of amyloid-b peptide, the plaque-producing protein fragment implicated in Alzheimer’s disease.

Nicotine, long known to have a neuro-protective role despite its other drawbacks, apparently uses JAK2 to enable this protection. "When brain cells are exposed to beta amyloid that makes plaque, nicotine protects them by activating JAK2, which activates a pathway of cell survival and blocks the beta activation of the pathway that leads to cell death," says Dr. Marrero, who discovered nicotine’s ability to regulate JAK2 in collaboration with Dr. Merouane Bencherif, vice president of preclinical research at the North Carolina-based pharmaceutical company, Targacept, Inc.

But if angiotensin II – a powerful vasoconstrictor involved in blood pressure regulation and a growth factor as well – is added to the mix, nicotine no longer protects brain cells. "Angiotensin II doesn’t allow JAK2 to be activated by nicotine," Dr. Marrero says.

This finding supports his theory that nicotine protects neurons through the JAK2 pathway but also points toward new treatment approaches for Alzheimer’s and other age-related dementias. One such treatment may be a drug that activates JAK2 in combination with ACE, or angiotensin converting enzyme, inhibitors which block angiotensin II production. ACE inhibitors are widely used to treat high blood pressure and anecdotal evidence indicates that people who take these drugs are less susceptible to Alzheimer’s and other dementias.

"What we are working on is trying to understand these pathways that lead to neuro-protection," says Dr. Marrero. "And how does angiotensin II block that action via JAK2? It may even be that JAK2 plays a role when angiotensin II acts as a growth factor." Dr. Marrero’s work on nicotine neuro-protection and JAK2 was published in the Nov. 22, 2002 issue of The Journal of Biological Chemistry.

His lab is also delineating the "bad" and "ugly" pathways that lead to JAK’s role in cell death and destructive proliferation. Like nicotine, its partner in neuro-protection, JAK2 is bad for blood vessels. When activated, JAK2 attacks blood vessels from the inside and out, prompting suicide of the endothelial cells that comprise the smooth interior through which blood flows and proliferation of the smooth muscle cells that comprise the exterior. The result is diseased, dysfunctional blood vessels.

JAK2 activation also is stimulated by high glucose levels in the body, a hallmark of diabetes, via the polyol pathway, a finding Dr. Marrero’s lab in collaboration with Dr. Carlos Isales, MCG endocrinologist, reported in the Aug. 15, 2003 issue of The Journal of Biological Chemistry. "That is why diabetics have a lot of blood vessel problems, in the aorta and major blood vessels," Dr. Marrero says.

In the face of high glucose, the kidneys are an easy target for JAK2’s detrimental effects, prompting glomeruli mesangial cells to grow and proliferate, thereby clogging the kidneys’ intricate filtering mechanisms, according to his work published in the December 2002 issue of Diabetes. "That is why diabetes is one of the main causes of kidney failure. If you take away high glucose, it doesn’t really happen," the researcher says.

Dr. Marrero is collaborating with Dr. David Pollock, MCG physiologist, to further explore what happens in the kidney in an animal model and with Dr. Patricia Schoenlein, an MCG cancer researcher, to explores JAK2’s apparent interference with some cancer therapies. For example, tamoxifen, an anti-estrogen that prompts breast cancer cell suicide, won’t work in cells containing insulin because insulin apparently activates JAK2, which intervenes. When the researchers add a known JAK inhibitor, AG4-90, tamoxifen works in those cells.

"We are trying to figure out how various compounds might be able to regulate JAK," says Dr. Marrero. "We know nicotine activates it, which is why we are studying it." He wants to find additional compounds that activate or inhibit JAK2 so he can maximize the protective qualities of the enzyme and eliminate its contributions to diseases such as diabetes.

Dr. Marrero recently co-authored the preface of a textbook scheduled for release later this month, "Diabetes and Cardiovascular Disease: Integrating Science and Clinical Medicine," with Dr. David M. Stern, a renowned diabetes and vascular researcher and dean of the MCG School of Medicine. The book is being published by Lippincott Williams & Wilkins, an international publisher of professional health information for physicians, nurses and students headquartered in Philadelphia.


###
Dr. Marrero’s research is funded by the National Institutes of Health, an American Heart Association Established Investigator Award grant and Targacept, Inc.

Toni Baker | EurekAlert!
Further information:
http://www.mcg.edu/

More articles from Health and Medicine:

nachricht Hepatitis: liver failure attributable to compromised blood supply
19.12.2018 | Technische Universität München

nachricht Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering

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: New megalibrary approach proves useful for the rapid discovery of new materials

Northwestern discovery tool is thousands of times faster than conventional screening methods

Different eras of civilization are defined by the discovery of new materials, as new materials drive new capabilities. And yet, identifying the best material...

Im Focus: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Scientists to give artificial intelligence human hearing

19.12.2018 | Information Technology

Newly discovered adolescent star seen undergoing 'growth spurt'

19.12.2018 | Physics and Astronomy

From a plant sugar to toxic hydrogen sulfide

19.12.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>