Francesca Marassi, PhD, professor and chair of biophysics at the Medical College of Wisconsin (MCW), received a five-year, $13 million Program Project Grant (PPG) from the National Institutes of Health (NIH) to study calcification misplaced in the eyes and brain of patients with Macular degeneration (AMD) and Alzheimer’s disease (AD).
AMD affects nearly 20 million adults in the United States and is the leading cause of central vision loss and legal blindness. More than 6 million people in the United States suffer from Alzheimer’s disease, the leading cause of dementia worldwide. Age is an important risk factor for these diseases. How AMD and AD progress over time is not well understood, and research is needed to drive the development of effective pharmaceutical treatments.
Both diseases are associated with the progressive accumulation of pebble-like deposits under the retina and in the brain. These deposits are known to contain cholesterol, fats (lipids), proteins and a mineralized form of calcium phosphate called hydroxyapatite – the same material that forms healthy teeth and bones. Scientists don’t yet know what causes these stray mineral deposits to form in the eye and brain. The healthy biological processes of calcification are meant to grow and repair bones and teeth, not to clutter the retina or brain with harmful waste. Understanding how and why these wayward biomineral deposits form can provide clues to better understand AMD and AD, as well as the development of new ways to diagnose and treat these diseases.
Since the eye and the brain are intimately linked as integral parts of the central nervous system, Dr. Marassi and his international team of PPG scientists will explore the characteristics of misplaced calcifications in both organs, as well as their roles in AMD and MY. A central goal is to examine and image calcifications at multiple levels, from atom-by-atom structures to their aggregate morphologies, and their accumulation in cells and animals.
I am really enthusiastic about the idea of exploring these pathological pathologies at all scales, from the atomic to the animal. This kind of structural information is essential to advance in diagnostics and drug development.”
Francesca Marassi, PhD, Professor and Chair of Biophysics at the Medical College of Wisconsin
The PPG team includes Galia Debelouchina, PhD, University of California San Diego; Jose Luis Millan, PhD, Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA); Richard Thompson, PhD, University of Maryland School of Medicine (Baltimore); and Imre Lengyel, PhD, Queen’s University Belfast. Led by Dr. Marassi, they designed four PPG projects to achieve their scientific goals.
“Our collaboration program is truly synergistic, with each team member bringing unique expertise and technology to the partnership,” Marassi said. “While the primary goal is to do excellent basic science that provides fundamental insights into misplaced calcification in disease, we believe there is enormous potential for these advances to provide a basis for new diagnostic techniques. and new treatments in the future, as the motto MCW best expresses knowledge changes life.”
The first project, led by Drs. Marassi and Debelouchina, will focus on the molecular structure and function of misplaced calcified deposits and their components. Their research teams will use sophisticated biophysical techniques to reveal the composition of these deposits and their formation by examining the interactions between proteins, cholesterol, fats and mineral components of the pebble-like deposits.
Dr. Thompson will lead the second project to develop and test new methods to tag biominerals in deposits with small molecules that cause the minerals to emit specific colors or wavelengths of light that scientists can detect in the images. . These fluorescent and luminescent sensors will serve as research tools for other projects and could eventually lead to new diagnostic and monitoring tools for AMD and AD.
The third project, led by Dr. Lengyel, aims to develop new cellular models of calcifications that mimic deposits found in animals and humans. His team will study how the levels of certain proteins, genetic predispositions and other factors influence the formation of deposits.
Dr. Millan leads the fourth project to study how cells and tissues maintain their balance of phosphorus levels, which is essential for healthy bone development. In adult humans, about 90% of the body’s total phosphorus is contained in bone as hydroxyapatite crystals, which are also part of the errant calcified deposits that form in AMD and AD. Dr. Millan’s team will study mice that overproduce an enzyme to determine how its control of phosphorus levels contributes to the formation of calcified deposits in the eye.
The PPG grant is funded by the National Institute of Aging and titled “Molecular Mechanisms of Calcification: Roles and Opportunities in Diseases of Aging.” In addition to the four projects, the grant will fund a protein and chemical biology core that will develop and deliver reagents for the PPG experiments, and an administrative core that will facilitate interactions between the laboratories of the PPG team.
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