Degenerative Diseases Program Archives - Sanford Burnham Prebys

Tag: Degenerative Diseases Program

Institute News

Yasuyuki Kihara wins a dream award

AuthorMiles Martin
Date

November 9, 2022

Yasuyuki Kihari, a Japanese man in a grey hoodie, holding his award, a clear crystal plate.

And he’s had his eye on it for more than a decade.

Research Assistant Professor Yasuyuki Kihara, PhD, has won an Eicosanoid Research Foundation (ERF) Young Investigator Award, which is presented every other year to three early-career faculty researchers who have made breakthroughs in the field of bioactive lipids.

The award may not come with a cash prize, but for Kihara, this prize is priceless. 

“The first time I applied for this award was around 2009, and I’ve applied several times since then,” he says. “This has been many years in the making, and I’m incredibly honored to receive this award.”

Kihara is the first Sanford Burnham Prebys scientist to win this award for research completed at the Institute. Assistant Professor Victoria Blaho, PhD, also received the award in 2007, before becoming a Sanford Burnham Prebys faculty member in 2019. 

Applying bioactive lipids to multiple sclerosis: Kihara’s prize-winning research

Kihara has devoted his scientific career of more than 20 years to studying bioactive lipids, a broad group of molecules that cells use to communicate and to control their activities. Some of the most well-known examples of bioactive lipids are the hormones testosterone and estrogen, but there are countless other examples in different parts of the body as well.

“Bioactive lipids are involved in signaling in every cell of every organism,” says Kihara. “Lipids are essential for life, and I’m not sure I could even imagine a biological process or a pathway that doesn’t involve a lipid at some step.”

Kihara’s work focuses on multiple sclerosis (MS), a potentially disabling disease of the brain and spinal cord that affects the brain’s ability to communicate with the rest of the body. MS occurs when protective structures in our neurons, called myelin sheaths, become damaged.

“Losing this myelin makes it much more difficult for the brain to send signals to other parts of the body,” says Kihara. “This causes a wide range of symptoms that can be debilitating for the people living with this disease.” 

In 2010, FDA-approved an oral drug for MS called fingolimod. Fingolimod has a chemical structure that resembles a bioactive lipid, and Kihara has teamed up with Professor Jerold Chun, MD, PhD, to study how this drug works at the molecular level to explore whether there may be other ways to leverage bioactive lipids against MS.

“We believe that cellular signaling pathways and the bioactive lipids that control them may have a more complicated role in MS than is currently understood,” says Kihara. “Studying these molecules at this fundamental level will help reveal new ways of treating the disease.”

Institute News

Jerold Chun receives a very special Alzheimer’s grant

AuthorMiles Martin
Date

May 13, 2022

Jerold Chun, MD, PhD

Jerold Chun, MD, PhD, has been awarded a new grant for $250,000 from the Coins for Alzheimer’s Research Trust (CART) Fund, an initiative by Rotary International to encourage exploratory and developmental Alzheimer’s research projects. Chun’s two-year project will explore how virus-like elements in our DNA could play a role in the development of Alzheimer’s disease.

“We are so grateful for the support of CART and the Rotarians,” says Chun. “They’ve shown over the years that small contributions to Alzheimer’s research can add up to make a huge impact.”

Ancient viruses in our genome
Chun’s project will explore how Alzheimer’s disease relates to endogenous genes in our genome that are very similar to parts of modern viruses. This is because they originated from viruses that infected our ancient ancestors. Over millions of years of evolution, these viruses became a normal part of our genomic makeup. 

Chun and other researchers suspect that these viral-like genes may be able to form virus-like particles that move through connections among our brain cells. They hypothesize that this process could promote neurodegenerative diseases like Alzheimer’s. “This new grant from CART will help us figure out how these genes and particles work, which is a first step toward thinking about how we might leverage it for treatments.”

Funding research with spare change
CART began in the mid-1990s with an ambitious idea: Could collecting the pocket change of Rotary International members accumulate enough to support Alzheimer’s disease?

The idea was launched in 1996 at Rotary Clubs in South Carolina; and at every meeting, members were asked to donate their loose change to a fund for Alzheimer’s research. The idea exploded from there. Over time, individual clubs started donating portions of their fundraising proceeds, and donations even began to come in from non-Rotary members as CART’s reputation grew.

The fund has awarded more than $10 million in grants to more than 40 institutions since its inception. This year, one of those grants was awarded to Chun to explore a new direction for Alzheimer’s research. This is the first CART grant to be awarded to a Sanford Burnham Prebys researcher.

“Grants like this are important because they give scientists the resources to pursue brand-new research areas,” says Chun. “Every major scientific discovery starts somewhere, and this type of support gives us that starting place, for which we’re really grateful.”

Institute News

Randal Kaufman among world’s most influential biologists

Authorkcusato
Date

February 4, 2016

dr. randal kaufman

Thomson Reuters has announced the world’s most influential scientific minds, and for the second time since 2014, Randal Kaufman, Ph. D., professor and director of SBP’s Degenerative Disease Program, is on that list. Thomson Reuters created the list based on scientists who write the most reports that rank among the top 1 percent cited by other scientists between the years 2003 and 2013. Analysts looked at more than 120,000 papers and recognized close to 3000 scientists.

Continue reading “Randal Kaufman among world’s most influential biologists”

Institute News

Antioxidant-rich diet could help stave off type 2 diabetes

AuthorGuest Blogger
Date

November 12, 2015

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Type 2 diabetes affects about 8% of all adults and is a leading cause of death worldwide. Despite its prevalence, relatively little is known about underlying molecular causes of the disease. SBP researchers now show that defects in a major cell stress pathway play a key role in the failure of pancreatic beta cells, leading to signs of diabetes in mice. The findings, published recently in PLOS Biology, also suggest that a diet rich in antioxidants could help to prevent or treat type 2 diabetes.

“The findings open new therapeutic options to preserve beta cell function and treat diabetes,” said senior study author Randal Kaufman, PhD, director of the Degenerative Diseases Program at SBP. “Because the same cell stress response is implicated in a broad range of diseases, our findings suggest that antioxidant treatment may be a promising therapeutic approach not only for metabolic disease, but also neurodegenerative diseases, inflammatory diseases, and cancer.”

Excess cell stress

Type 2 diabetes is caused by the failure of pancreatic beta cells to produce enough insulin—a hormone that helps to move a blood sugar called glucose into cells to be stored for energy. A major cause of type 2 diabetes is obesity, which can lead to abnormalities in insulin signaling and high blood glucose levels. Beta cells try to compensate by producing up to 10 times the usual amount of insulin, but this puts extra stress on a cell structure called the endoplasmic reticulum to properly fold, process, and secrete the hormone.

An increase in protein synthesis in beta cells also causes oxidative stress—a process that can lead to cell damage and death through the build-up of toxic molecules called reactive oxygen species. If the stress is too great, the beta cells will eventually fail. Approximately one-third of individuals with abnormal insulin signaling eventually develop beta cell failure and diabetes.

In the new study, Kaufman and his collaborators discovered that beta cell failure is caused by deficiency in a protein called IRE1α, which would otherwise help to protect cells against the stress of increased insulin production. Mice that lacked IRE1α in pancreatic beta cells did not produce enough insulin and developed high blood glucose levels, similar to patients with type 2 diabetes. IRE1α deficiency also caused inflammation and oxidative stress, which was the primary cause of beta cell failure. But treatment with antioxidants, which prevented the production of reactive oxygen species, significantly reduced metabolic abnormalities, inflammation and oxidative stress in these mice.

Taken together, the findings suggest that IRE1α evolved to expand the capacity of beta cells to produce insulin in response to increases in blood glucose levels. The study also implicates this major cell stress pathway in the development of type 2 diabetes and suggests that a diet rich in antioxidants could help to prevent or reduce the severity of the disease.

“Currently, we are testing the effects of antioxidants on glucose levels and beta cell function in mice,” Kaufman said. “If these studies prove successful, they could pave the way for clinical trials in humans and eventually lead to a new therapeutic approach for dealing with a major pandemic of the 21st century.”

This post was written by guest blogger Janelle Weaver, PhD

Institute News

Sanford-Burnham presents at the 2014 Society for Neurosience Meeting

Authorsgammon
Date

November 13, 2014

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The Society for Neuroscience’s 44th annual meeting is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations, and learn about new technologies and tools. Sanford-Burnham has several dynamic research programs in neuroscience, and below are our presentations scheduled for this year’s event. Continue reading “Sanford-Burnham presents at the 2014 Society for Neurosience Meeting”

Institute News

Why people with Down syndrome invariably develop Alzheimer’s disease

Authorsgammon
Date

October 23, 2014

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A new study by researchers at Sanford-Burnham reveals the process that leads to changes in the brains of individuals with Down syndrome—the same changes that cause dementia in Alzheimer’s patients. The findings, published in Cell Reports, have important implications for the development of treatments that can prevent damage in neuronal connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions, including Alzheimer’s disease.

Down syndrome is characterized by an extra copy of chromosome 21 and is the most common chromosome abnormality in humans. It occurs in about one per 700 babies in the United States, and is associated with a mild to moderate intellectual disability. Down syndrome is also associated with an increased risk of developing Alzheimer’s disease. By the age of 40, nearly 100 percent of all individuals with Down syndrome develop the changes in the brain associated with Alzheimer’s disease, and approximately 25 percent of people with Down syndrome show signs of Alzheimer’s-type dementia by the age of 35, and 75 percent by age 65. As the life expectancy for people with Down syndrome has increased dramatically in recent years—from 25 in 1983 to 60 today—research aimed to understand the cause of conditions that affect their quality of life are essential.

“Our goal is to understand how the extra copy of chromosome 21 and its genes cause individuals with Down syndrome to have a greatly increased risk of developing dementia,” said Huaxi Xu, PhD, professor in the Degenerative Diseases Program and senior author of the paper. “Our new study reveals how a protein called sorting nexin 27 (SNX27) regulates the generation of beta-amyloid—the main component of the detrimental amyloid plaques found in the brains of people with Down syndrome and Alzheimer’s. The findings are important because they explain how beta-amyloid levels are managed in these individuals.”

Beta-amyloid, plaques, and dementia

Xu’s team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is a sticky protein that’s toxic to neurons. The combination of beta-amyloid and dead neurons form clumps in the brain called plaques. Brain plaques are a pathological hallmark of Alzheimer’s disease and are implicated in the cause of the symptoms of dementia.

“We found that SNX27 reduces beta-amyloid generation through interactions with gamma-secretase—an enzyme that cleaves the beta-amyloid precursor protein to produce beta-amyloid,” said Xin Wang, PhD, a postdoctoral fellow in Xu’s lab and first author of the publication. “When SNX27 interacts with gamma-secretase, the enzyme becomes disabled and cannot produce beta-amyloid. Lower levels of SNX27 lead to increased levels of functional gamma-secretase that in turn lead to increased levels of beta-amyloid.”

SNX27’s role in brain function

Previously, Xu and colleagues found that SNX27-deficient mice shared some characteristics with Down syndrome, and that humans with Down syndrome have significantly lower levels of SNX27. In the brain, SNX27 maintains certain receptors on the cell surface—receptors that are necessary for neurons to fire properly. When levels of SNX27 are reduced, neuron activity is impaired, causing problems with learning and memory. Importantly, the research team found that by adding new copies of the SNX27 gene to the  brains of Down syndrome mice, they could repair the memory deficit in the mice.

The researchers went on to reveal how lower levels of SNX27 in Down syndrome are the result of an extra copy of an RNA molecule encoded by chromosome 21 called miRNA-155. miRNA-155 is a small piece of genetic material that doesn’t code for protein, but instead influences the production of SNX27.

With the current study, researchers can piece the entire process together—the extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase in the amount of active gamma-secretase causing an increase in the production of beta-amyloid and the plaques observed in affected individuals.

“We have defined a rather complex mechanism that explains how SNX27 levels indirectly lead to beta-amyloid,” said Xu. “While there may be many factors that contribute to Alzheimer’s characteristics in Down syndrome, our study supports an approach of inhibiting gamma-secretase as a means to prevent the amyloid plaques in the brain found in Down syndrome and Alzheimer’s.”

“Our next step is to develop and implement a screening test to identify molecules that can reduce the levels of miRNA-155 and hence restore the level of SNX27, and find molecules that can enhance the interaction between SNX27 and gamma-secretase. We are working with the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham to achieve this,” added Xu.

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 This research was supported in part by US NIH/National Cancer Institute Grant AG038710, AG021173, NS046673, AG030197 and AG044420, and grants from the Alzheimer’s Association, the Global Down Syndrome Foundation, the BrightFocus Foundation (formerly the American Health Assistance Foundation) and the National Natural Science Foundation of China.

To link to the paper click: http://www.cell.com/cell-reports/abstract/S2211-1247(14)00820-1

Institute News

Dr. Randal Kaufman, one of the world’s most influential scientific minds

Authorsgammon
Date

July 18, 2014

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Last week, Thomson Reuters published a list of the world’s most influential scientific minds—195 of them in biology and biochemistry to be exact. Thomson Reuters created the list based on scientists that write the most reports that rank among the top 1 percent cited by other scientists between the years 2002 and 2012. To no surprise from us at Sanford–Burnham, Randal Kaufman, PhD, professor and director of the Degenerative Disease Program, was on the list.

Dr. Kaufman has been a major contributor to our understanding of how protein folding—and misfolding—lead to cell malfunctions and death. His research is particularly important to many diseases, including neurological, metabolic, genetic and inflammatory disorders. His research also explains some of the symptoms associated with aging.

Dr. Kaufman has a long history of contributions to science in industry and academia. As PhDgraduate student at Stanford University, he discovered that cancer cells develop drug resistance by gene amplification. As a post-doctoral fellow working with Nobel laureate Dr. Phillip Sharp at MIT, he studied gene amplification and new ways to express proteins in mammalian cells.

After post-doctoral work, Dr. Kaufman co-founded a company called the Genetics Institute Inc., a biotechnology company focused on treatments for hemophilia and many other disorders, including the development of technology that led to the FDA-approved drugs for hemophilia and erythropoietin for cancer and anemia.  After leaving the Genetics Institute, Inc. he took a position as HHMI investigator and endowed chair in the departments of Biological Chemistry and Internal Medicine at the University of Michigan.  He joined us at Sanford-Burnham in 2011 where he leads the Degenerative Disease Program.

Let us all take advantage of the fact that we have this incredible individual at our Institute and discover five interesting facts about the man with the brilliant brain.

If you could invite 5 people to dinner who would they be?Albert Einstein, Steve Jobs, Charles Darwin, Princess Diana and Brian Williams

What traits do  you most admire in people?Intelligence, confidence, and a sense of humor

What traits do you most deplore in people? Laziness, conceit and selfishness

What is your idea of a perfect weekend in San Diego? Sailing with my wife, Donna and three boys, Joshua, Kyle, and Maverick

If a genie granted you three wishes, what would they be? World peace, a cure for cancer, and unlimited NIH support for my research

From all of us at Sanford-Burnham, we congratulate you Dr. Kaufman and we hope your wishes come true!