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Plaque Presents Nanotech Research Challenge

Photonics.com
May 2005
ATLANTA, May 4 -- Biomedical nanotechnology might help shed light on the molecular mechanisms responsible for plaque buildup that can lead to heart disease.

The National Institutes of Health (NIH) has awarded researchers from Georgia Institute of Technology and Emory University $11.5 million to establish a new research program to create advanced nanotechnologies to analyze plaque formation on the molecular level and to detect plaque at its early stages.

Atherosclerosis, or the narrowing of arteries due to the buildup of plaque along the inner lining, is the single most lethal condition in the US, yet there is a lack of understanding of plaque's fundamental molecular biology and how certain genetic factors contribute to plaque buildup in blood vessels. Plaques are a composite of fat and cholesterol deposits as well as blood platelets, decomposing muscle cells and other tissue. They may build up in blood vessels over time; when they become unstable and rupture, they can block the vessels, leading to heart attack and stroke. Healthy, undamaged cells lining the vessel wall do not attract platelets or cause a buildup of plaque. But in a diseased blood vessel, cells lining the vessel wall may have certain cellular and molecular characteristics that make them stickier, causing platelets to stick to the vessel wall, create plaque blockage and obstruct blood flow.

The NIH award is part of its National Heart, Lung, and Blood Institute's Program of Excellence in Nanotechnology, or PEN, headed by Gang Bao, a professor of biomedical engineering at Georgia Tech and Emory. It includes 12 faculty investigators from both institutions and will be based at Emory. The program, one of four national PEN awards, is part of an NIH strategy to accelerate progress in medical research through innovative technology and interdisciplinary research. It will focus primarily on detecting plaque and pinpointing its genetic causes with three types of nanostructured probes: molecular beacons, semiconductor quantum dots and magnetic nanoparticles.

Hairpin Loops and QDot Probes

A molecular beacon is a biosensor about four to five nanometers in size that can seek and detect specific target genes. It is a short piece of single-stranded DNA (ssDNA) in the shape of a hairpin loop with a fluorescent dye molecule at one end and a "quencher" molecule at the other. The ssDNA is synthesized to match a region on a specific messenger RNA (mRNA) that is unique to the gene. The fluorescence of the beacon is quenched, or suppressed, until it seeks out and binds to a complementary target mRNA, which causes the hairpin to open up and the beacon to emit light.

The level of gene expression within a cell can reflect susceptibility to disease. The fluorescence from the beacons will vary with the level of the target genes’ expression in each cell, creating a glowing marker if the cell has a detectable level of gene expression that is known to contribute to cardiovascular disease.

"With molecular beacons, we hope to follow the dynamics of gene expression in normal and diseased cells," Bao said. "We can find out how quickly these genes are being turned on and how the expression levels are correlated with factors contributing to early plaque formation."

To complement gene expression studies using molecular beacons, the team will develop quantum-dot nanocrystal probes and use them to study protein molecular signatures of cardiovascular disease. Quantum dots, or Qdots, are nanometer-sized semiconductor particles that have unique electronic and optical properties, due to their size and their highly compact structure. Qdot-based probes can act as markers for specific proteins and cells and can be used to study protein-protein interactions in live cells or to detect diseased cells. These ultrasensitive probes may help cardiologists understand the formation of early-stage plaques and dramatically improve detection sensitivity.

Other research will include using magnetic nanoparticles to detect early-stage plaques in patients. The magnetic nanoparticles will target specific proteins on the surface of cells in a plaque and will serve as a contrast agent in magnetic resonance imaging (MRI). This could provide an image of the plaque formation and could become a powerful tool for better disease diagnosis. The investigators will also develop ultrasensitive probes for the free radicals inside cells and biomolecular constructs for molecular imaging and therapeutics.

In addition to this cardiovascular nanotechnology award and an ongoing cancer nanotechnology program, the Georgia Tech/Emory group also plans to expand biomolecular engineering and nanotechnology to the detection and treatment of other conditions, such as neurodegenerative and infectious diseases.

Co-investigators include Emory cardiologists Wayne Alexander, Kathy Griendling, David Harrison, Charles Searles and Robert Taylor, and biomedical engineers from Georgia Tech and Emory: Don Giddens, Xiaoping Hu, Hanjoong Jo, Niren Murthy, Shuming Nie and Dongmei Wang.

For more information, visit: www.gatech.edu



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