Potential 'fountain of youth' gene found

Gene helps prevent heart attack, stroke; may offer way to block effects of aging

Date:

May 17, 2016

Source:

University of Virginia Health System

Summary:

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

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This is an atherosclerotic lesion. Such lesions can rupture and cause heart attacks and strokes.

Credit: UVA School of Medicine

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers at the University of Virginia School of Medicine have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

"Finding a way to augment the expression of this gene in adult cells may have profound implications for promoting health and possibly reversing some of the detrimental effects with aging," said researcher Gary K. Owens, PhD, director of UVA's Robert M. Berne Cardiovascular Research Center.

Unexpected Protective Effect

The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but the UVA researchers are the first to provide conclusive evidence of that: Owens and his colleagues have determined the gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes.

The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous "caps" inside the plaques -- caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques. This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. "Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques," said Olga A. Cherepanova, PhD, a senior research scientist in Owens' lab.

One surprising finding from UVA's research: When the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable and more dangerous, stuffed with lipids, dead cells and other damaging components.

Advancing Regenerative Medicine

While UVA's research has focused on how Oct4 offers cardiovascular protection, Owens and his colleagues believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells -- the non-reproductive cells in the body -- and play a key role in the cells' ability to repair damage and heal wounds. Studies to test this are under way in Owens' lab.

Oct4 is one of the "stem cell pluripotency factors" described by Shinya Yamanaka, MD, PhD, for which he received the 2012 Nobel Prize. His lab and many others have shown that artificial over-expression of Oct4 within somatic cells grown in a lab dish is essential for reprogramming these cells into induced pluripotential stem cells, which can then develop into any cell type in the body or even an entire organism.

The UVA researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. "Finding a way to reactivate this pathway may have profound implications for health and aging," Owens said. "We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine. Who knows, this may end up being the 'fountain-of-youth gene,' a way to revitalize old and worn-out cells. Only time will tell."

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Story Source:

The above post is reprinted from materials provided by University of Virginia Health System. Note: Materials may be edited for content and length.

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Journal Reference:

1. Olga A Cherepanova, Delphine Gomez, Laura S Shankman, Pamela Swiatlowska, Jason Williams, Olga F Sarmento, Gabriel F Alencar, Daniel L Hess, Melissa H Bevard, Elizabeth S Greene, Meera Murgai, Stephen D Turner, Yong-Jian Geng, Stefan Bekiranov, Jessica J Connelly, Alexey Tomilin, Gary K Owens. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nature Medicine, 2016; DOI:10.1038/nm.4109

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Chemists develop an ultra-sensitive test for cancers, HIV

A common theme in medicine is that detecting a disease early on can lead to more effective treatments. This relies partly on luck that the patient gets screened at the right time, but more important is that the testing techniques are sensitive enough to register the minuscule hints that diseases leave in the blood stream.

A new technique developed by a team of chemists at Stanford has shown promise to be thousands of times more sensitive than current techniques in lab experiments, and it is now being put to test in real-world clinical trials.

When a disease -- whether it's a cancer or a virus like HIV -- begins growing in the body, the immune system responds by producing antibodies. Fishing these antibodies or related biomarkers out of the blood is one way that scientists infer the presence of a disease. This involves designing a molecule that the biomarker will bind to, and which is adorned with an identifying "flag." Through a series of specialized chemical reactions, known as an immunoassay, researchers can isolate that flag, and the biomarker bound to it, to provide a proxy measurement of the disease.

The new technique, developed in the lab of Carolyn Bertozzi, a professor of chemistry at Stanford, augments this standard procedure with powerful DNA screening technology. In this case, the chemists have replaced the standard flag with a short strand of DNA, which can then be teased out of the sample using DNA isolation technologies that are far more sensitive than those possible for traditional antibody detections.

"This is spiritually related to a basic science tool we were developing to detect protein modifications, but we realized that the core principles were pretty straightforward and that the approach might be better served as a diagnostic tool," said Peter Robinson, a co-author on the study and graduate student in Bertozzi's group.

The researchers tested their technique, with its signature DNA flag, against four commercially available, FDA-approved tests for a biomarker for thyroid cancer. It outperformed the sensitivity of all of them, by at least 800 times, and as much as 10,000 times. By detecting the biomarkers of disease at lower concentrations, physicians could theoretically catch diseases far earlier in their progression.

"The thyroid cancer test has historically been a fairly challenging immunoassay, because it produces a lot of false positives and false negatives, so it wasn't clear if our test would have an advantage," Robinson said. "We suspected ours would be more sensitive, but we were pleasantly surprised by the magnitude."

Putting basic research to use in a clinical setting has been a focus of Bertozzi's since she arrived at Stanford.

"I moved to Stanford with the anticipation that translation of my students' innovations to clinically impactful products and technologies would be enabled," said Bertozzi, who is a faculty fellow of Stanford ChEM-H, as well as a professor, by courtesy, of radiology and of chemical and systems biology. "That goal is being delightfully fulfilled."

Based on the success of the thyroid screening, the group has won a few grants to advance the technique into clinical trials. One trial underway in collaboration with the nearby Alameda County Public Health Laboratory will help evaluate the technique as a screening tool for HIV. Early detection and treatment of the virus can help ensure that its effects on the patient are minimized and reduce the chance that it is transmitted to others. This effort is supported by a pilot grant from Stanford-Spectrum, funded by the National Center for Advancing Translational Sciences at the National Institutes of Health.

"Many of our collaborators are excited that the test can be readily deployed in their lab," said co-author Cheng-ting "Jason" Tsai, a graduate student in Bertozzi's group. "In contrast to many new diagnostic techniques, this test is performed on pre-existing machines that most clinical labs are already familiar with."

The researchers are also pursuing tests for Type 1 diabetes, for which early detection could help patients manage the disease with fewer side effects.

The research is published in the journalACS Central Science. The study was co-authored by Carole Spencer of the University of Southern California. This work was supported in part by a grant from the National Institutes of Health.

Story Source:

The above story is based on materials provided by Stanford University. Note: Materials may be edited for content and length.

Journal Reference:

Cheng-ting Tsai, Peter V. Robinson, Carole A. Spencer, Carolyn R. Bertozzi.Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP). ACS Central Science, 2016; DOI: 10.1021/acscentsci.5b00340

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