calcification Archives - Sanford Burnham Prebys
Institute News

José Luis Millán joins international initiative to study calcification in aging

AuthorMiles Martin
Date

July 21, 2023

Sanford Burnham Prebys professor José Luis Millán, PhD, has joined a five-year, $13 million program that will study misplaced calcification in the eyes and brains of patients suffering from age-related macular degeneration (AMD) and Alzheimer’s disease (AD).

The initiative is funded by the National Institute on Aging and will be led by Francesca Marassi, PhD, an adjunct professor at Sanford Burnham Prebys and chair of biophysics at the Medical College of Wisconsin.

AMD affects nearly 20 million adults in the U.S. and is the leading cause of central vision loss and legal blindness. AD affects more than 6 million people in the U.S., and it is the top cause of dementia across the globe. Age is a prominent risk factor for both diseases. However, 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 mineralized deposits under the retina and in the brain. Healthy calcification processes are needed to grow and repair bones, but these same processes can cause misplaced deposits in the eye and the brain that contribute to disease. Scientists do not yet know what causes these deposits to form, and answering this question may provide clues to better understand AMD and AD, as well as aid the development of new ways to diagnose and treat these diseases.

The international research team, which also includes scientists from UC San Diego, University of Maryland School of Medicine, and Queen’s University Belfast, will explore the characteristics of misplaced calcifications in both the eye and the brain. They have devised four projects to examine calcifications at varying scales, from their atomic structure up to their accumulation in cells and animals.

Millan will direct the fourth project, which will study how cells and tissues maintain their balance of phosphorus. In human adults, approximately 90 percent of the body’s total phosphorus is crystalized in bone, and these same crystals also are part of the calcified deposits that form in AMD and AD. Dr. Millan’s team will study mice to determine how cells control phosphorus levels and how these biochemical pathways contribute to the formation of calcified deposits in the eye.


The grant, funded by the National Institute on Aging, is titled “Molecular mechanisms of calcification: roles and opportunities in diseases of aging.”

This story is adapted from a press release published by Medical College of Wisconsin.

Institute News

Where science meets patients: Sanford Children’s Research Center hosts inaugural symposium

AuthorMiles Martin
Date

May 10, 2023

The event celebrated 16 years of progress at the Center and connected scientists with the people most impacted by their work.

The Sanford Children’s Health Research Center at Sanford Burnham Prebys recently hosted its first-ever Children’s Health Research Symposium, which brought scientists and families together to learn about the latest research tackling childhood diseases.

“We’re all here because we want to improve the health of children,” said President and CEO David A. Brenner, MD, during his opening comments. “But this event also shows the amazing amount of collaboration and collegiality across San Diego, because we have all types of people together from different backgrounds who want to develop therapies and cures for children affected by disease.”

The Sanford Children’s Health Research Center was established in 2008 with the help of a generous gift from Institute namesake T. Denny Sanford. Since then, the Center has been a world leader in children’s health research.

“T. Denny Sanford made an investment in children’s health 15 years ago, and I think that investment has paid off pretty well so far,” said Center director Hudson Freeze, PhD, in his introduction to the first scientific session. Freeze is among the world’s leading experts on congenital disorders of glycosylation (CDG), a rare group of genetic disorders that can cause serious, sometimes fatal, malfunctions of different organs and systems in the body.

“We’ve published over 600 scientific papers, and about half of those are translational studies, which means they’re helping turn scientific discoveries into real treatments for patients,” adds Freeze.

Professor Hudson Freeze with the Omler family

Professor Hudson Freeze with the Omler family

The day included presentations from researchers at Sanford Burnham Prebys, as well as from other research organizations studying childhood diseases. However, the highlight of the event was the afternoon reception, in which scientists had the opportunity to mingle and share a meal with families affected by rare childhood diseases.

Professor José Luis Millán (center) with the Fischer family (left) and the Britt family (right)

Professor José Luis Millán (center) with the Fischer family (left) and the Britt family (right)

Each researcher briefly introduced the family affected by the illness the scientist studies. This list included many longtime friends of the Institute, such as Damian Omler, who lives with a rare form of CDG; and Morgan Fischer, who was born with soft bone disease. Today, thanks to the help of a drug developed based on the research of Institute professor José Luis Millán, PhD, Morgan is a thriving teenager. This drug is also helping other children living with soft bone disease, including 10-year-old Aubrey Britt, who was in attendance with her family as well.

“Something so important that we keep as a tradition for scientific events at our Institute is to involve families that have been touched by the work of our faculty,” said Freeze. “They’re why we’re all here.”

The full list of talks included: 

Sanford Children’s Health Research Center

  • José Luis Millán, PhD “Developing therapeutics for soft bones and ectopic calcification disorders”
  • Duc Dong, PhD “From hope for few to drug for many—why rare is precious”
  • Evan Snyder, MD PhD “A clinical trial using human neural stem cells for neuroprotection in perinatal asphyxia, a major cause of cerebral palsy in kids”
  • Anne Bang, PhD “Drug screens of human-induced pluripotent stem cell (hiPSC) derived neuronal networks on multi-electrode arrays”
  • Pamela Itkin-Ansari, PhD “Proinsulin misfolding in diabetes”
  • Yu Yamaguchi, MD PhD “Multiple hereditary exostoses—from genetics to potential drug targets”
  • Hudson Freeze, PhD “Fucose therapy: Revising bedrock biochemistry”

Sanford Health

  • David Pearce, PhD “From rare diseases to type-1 diabetes: Research that impacts children at Sanford Health”

Frontiers in Congenital Disorders of Glycosylation Consortium

  • Eva Morava, MD, PhD “Clinical trials in Glyco-land”
  • Ethan Perlstein, PhD “Precision drug repurposing: Patient avatar to pioneer study to Phase 3 trial”

UC San Diego

  • Lars Bode, PhD “Human milk-based therapeutics and diagnostics to protect preterm babies from necrotizing enterocolitis”
  • Stephanie Cherqui, PhD “Hematopoietic stem cell gene therapy for cystinosis: Mechanism of action and clinical trial update”
Institute News

Genes promote hardening of arteries in type 2 diabetes

Authorsgammon
Date

July 15, 2014

Type 2 diabetes has become a national epidemic, affecting nearly 26 million children and adults in the U.S. and approximately 170 million worldwide. According to the American Diabetes Association, $245 billion in costs are associated with diabetes, and 1 in 5 health-care dollars is spent caring for diabetics. A significant portion of the health costs associated with diabetes are those attributed to complications of the disease—including heart attacks, heart failure, stroke, dementia, chronic kidney disease, and amputations of the lower limbs. These complications emerge partly from hardening of the arteries caused by calcium deposits—a process known as arterial calcification—and are much more common in type 2 diabetics than in non-diabetics.

Dwight Towler, MD, PhD, professor and director of the Cardiovascular Pathobiology Program at Sanford-Burnham, has been actively researching the molecular causes of arterial calcification for more than a decade. Finding a way to prevent cardiovascular calcification could improve the vascular health of type 2 diabetes and prevent many of the associated medical complications.

In Towler’s previous work, he found that the assumption that arterial calcification was a natural, passive process that happens when cells die was incorrect. Instead, he showed that when the metabolism is disturbed—as in diabetes—calcium deposits are made by an active process that happens when key regulatory proteins erroneously trigger bone-formation genes in the arteries. Today, he is focused on those regulatory proteins, coded in the DNA by the Msx genes. Under normal conditions, Msx genes are essential for the formation of bones and teeth in the skull. But, in inflammatory conditions such as those associated with type 2 diabetes, the genes trigger the formation of calcium deposits in the arteries.

In his most recent study published on July 16 in the journal Diabetes, in collaboration with Dr. Robert Maxson of the University of Southern California, Towler’s research team examined the impact of Msx genes in mice genetically engineered to develop diabetes when fed high-fat diets. Previously, Towler showed how high-fat diets up-regulated the Msx genes in the aorta and coronary vessels of these mice, and caused calcium deposits via the Wnt paracrine signaling cascade. Now the question was: What would happen if Msx genes were absent in these mice?

“We were pleased to find that down-regulation of the Msx genes did indeed reduce the arterial calcification and vascular stiffness associated with diabetes,” said Towler. Our results are important because currently, there are no drugs to treat cardiovascular calcification. We have now identified four signaling pathways that represent targets for new drugs to intervene and inhibit the process.”

As a board-certified internist, Towler is committed to advancing these research findings to improve patient health and health care. “Our next step is to biochemically and genetically validate these pathways in human vascular disease—and identify drugs that improve vascular structure and function in mice. We are starting with lead compounds already tested in humans for other indications to see if we can repurpose those drugs to minimize the time it takes to get a treatment to the patients that suffer from this devastating complication of diabetes,” added Towler.

The study was performed in collaboration with the Norris Cancer Center, University of Southern California (CA),  Washington University in St. Louis (MO), the Translational Research Institute for Metabolism and Diabetes (FL), and MD Anderson Cancer Center (TX).

Funding for the study was provided by NIH grants HL69229 and HL81138, the Barnes-Jewish Hospital Foundation, and Sanford-Burnham Medical Research Institute.