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 Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

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: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>