AMED-funded projects

Project summaries 2020

Neurodegenerative disorders have more in common than meets the eye

An abnormal interaction between two proteins underpins a spectrum of neurodegenerative disorders

British physicist Stephen Hawking suffered from amyotrophic lateral sclerosis (ALS), which belongs to frontotemporal lobar degeneration (FTLD) spectrum disorders. An AMED-supported study has found that ALS and other FTLD spectrum disorders are connected through an abnormal interaction between two proteins.

© CORBIN O'GRADY STUDIO/SCIENCE PHOTO LIBRARY

A family of neurodegenerative disorders known as frontotemporal lobar degeneration (FTLD) spectrum disorders is linked by an abnormal interaction between two proteins, an AMED-funded study has found, despite the conditions exhibiting different symptoms.

FTLD spectrum disorders include FTLD, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). “From clinical and pathological points of view, these disorders have distinct features,” notes Shinsuke Ishigaki of Nagoya University Graduate School of Medicine. “For instance, ALS and PSP show quite different clinical symptoms, and thus they were considered to have different pathological backgrounds.”

But a team led by Ishigaki has shown that these neurodegenerative disorders have more in common than previously thought.

The researchers studied the interaction between two proteins — named fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) — in brain autopsy samples from over 100 deceased individuals with various FTLD spectrum disorders and in control samples. “Our results showed that there is potentially a common pathomechanism among FTLD spectrum disorders, even between ALS and PSP,” says Ishigaki.

This aberrant interaction leads to an imbalance of tau protein variants, which has been implicated in a wide range of neurodegenerative disorders. In contrast, the interaction between FUS and SFPQ produces a functional balance of tau isoforms in healthy individuals.

This finding could lead to new treatments. “We can design a treatment strategy for FTLD spectrum diseases that could target the factors involved in the process,” says Ishigaki.

Project: Development of molecular-targeted therapy and biomarker for disease-modifying therapy in FTLD

Researcher: Shinsuke Ishigaki

Host Institution: Nagoya University Graduate School of Medicine

AMED Funding: Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) and the Strategic Research Program for Brain Sciences (SRPBS)

Why a cell doesn’t attack its own DNA

The long-standing puzzle of why the immune system is not activated by a cell’s own DNA has been solved by a molecular-structure study

A computer-generated graphic showing the molecular structure of the cGAS–nucleosome complex. A structural study of the enzyme as cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) has shown why it does not bind to DNA in nucleosomes.

© 2021 Hitoshi Kurumizaka

A structural investigation of an enzyme that alerts the innate immune system to the presence of foreign DNA in a cell has revealed why the enzyme isn’t triggered by a cell’s own DNA. This finding will inform research into autoimmune disorders.

When foreign DNA enters a cell, an enzyme known as cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) senses the DNA by binding to it, which triggers an innate immune response. But researchers have long puzzled over why cGAS doesn’t bind to the cell’s own DNA.

Recently, researchers have found that the binding of cGAS to a nucleosome, which is the structure that spools a cell’s DNA, inactivates the response of cGAS to the cell’s DNA, thereby avoiding an autoimmune response. However, the mechanism behind the inactivation of cGAS remained unclear.

Now, in an AMED-funded study, Hitoshi Kurumizaka of the University of Tokyo and his co-workers have used cryo-electron microscopy to investigate the molecular structure of cGAS and nucleosome complex. They found that the three sites that cGAS uses to bind to DNA are either blocked or repurposed when cGAS binds to the nucleosome.

“We discovered that all three cGAS–DNA binding and dimerization sites, which are required for cGAS activation, become inaccessible when cGAS binds to the nucleosome,” says Kurumizaka. “Surprisingly, we found that one site that binds to DNA was repurposed and instead it bound to histones [components of the nucleosome].”

“We believe these results are of great interest to the immunology community since they significantly advance our understanding of the cGAS mechanism. Surprisingly, in the same day, four other groups published the cGAS-nucleosome complex structures with quite similar conclusion,” says Kurumizaka. “They may contribute to our knowledge of autoimmune diseases and help the development of new therapeutic drugs.”

Project: Production and characterization of reconstituted chromatin for epigenetics research and drug discovery

Researcher: Hitoshi Kurumizaka

Host Institution: The University of Tokyo

AMED Funding: Platform Project for Supporting Drug Discovery and Life Science Research (BINDS)

Intestinal inflammation alters clonal composition

Inflammation of the large intestine leads to the positive selection of specific gene mutations

A colored scanning electron micrograph of freeze-fractured bowel tissue from a patient suffering from ulcerative colitis. An AMED-funded study found that ulcerative colitis leads to a proliferation of cells containing certain mutations.

© STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY

Chronic inflammation of the intestines has been found to remodel the local cellular landscape and results in the proliferation of cells having certain mutations. This discovery could lead to new therapies for colorectal cancer.

Chronic inflammation involves accelerated destruction and repair of tissue and is associated with a higher risk of developing cancer. But it is not known how these recurring destroy-and-repair cycles affect the clonal composition of tissues and what role an altered clonal composition plays in the development of cancer.

In an AMED-funded study, Seishi Ogawa of Kyoto University and his co-workers have examined the clonal composition of people with ulcerative colitis—persistent inflammation of the large intestine, which is associated with an increased risk of cancer development. They found higher occurrences of certain gene mutations, but that these mutations differed from those that are positively selected in colitis-associated cancer.

This finding came as a surprise. “Unlike sun-exposed skin and esophageal epithelium in aged people, clonal expansion is rarely seen in the colorectal epithelium of healthy individuals, even in aged individuals,” says Ogawa. “Surprisingly, however, in ulcerative colitis patients, the colorectal epithelium underwent extensive remodelling by expansion of numerous independent clones, which are accompanied by several recurrent mutations and are thus positively selected.”

“Our finding provides insight into how our body responds to an inflammatory insult and also into how the positive-selection mechanism differs between inflammation and carcinogenesis,” adds Ogawa. This knowledge can be used to identify vulnerabilities in cancer development that could be exploited by new therapies.

Project: Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Researcher: Seishi Ogawa

Host Institution: Kyoto University

AMED Funding: Project for Development of Innovative Research on Cancer Therapeutics, Core Research for Evolutional Science and Technology (CREST)

Coffee drinking might be in your genes

Certain genetic variants exhibit associations with the eating and drinking habits of Japanese people

A genome-wide association study (GWAS) has found that people with certain genetic variants are more likely to drink coffee.

© Tom Werner/Getty

Nine gene locations that make a person more predisposed to consume certain foods (such as yogurt and fish) and beverages (including coffee and alcohol) have been identified in a genome-wide association study (GWAS).

GWAS have been extensively used to identify connections between gene variants and diseases. But until now they have not been used to determine the links between our genes and eating habits.

Now, in an AMED-funded study, Yukinori Okada of Osaka University and his co-workers have compared genetic data from more than 160,000 Japanese people with the consumption of 13 foods and drinks. From this comparison, they identified nine gene locations that had significant associations with the consumption of the foods and drinks. Ten of the associations they found had not been reported previously.

The researchers were surprised at how many gene variants were associated with consumption habits. “While some of these variants were previously known to be associated with drinking alcohol, we didn’t expect that so many of the variants would be associated with a wide range of dietary habits,” says Okada.

One gene variant was associated with many different food and drink preferences: people with a variation in a single DNA nucleotide at one specific gene were likely to consume more milk, yogurt, coffee and green tea but less alcohol, fish, tofu and fermented soybeans. “It was interesting that one variant at the ALDH2 gene affected so many dietary habits,” says Okada.

“Our study revealed that what we eat (in other words, our dietary habits) is defined by what we are (that is our, genetics),” he adds.

Project: GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits

Researcher: Yukinori Okada

Host Institution: Osaka University

AMED Funding: Tailor-Made Medical Treatment Programme (BioBank Japan, BBJ), Strategic Research Programme for Brain Sciences

Antiviral-resistant influenza viruses are no less virulent

Resistance to an antiviral drug does not seem to put flu viruses at any disadvantage compared to their susceptible cousins

A scanning electron micrograph of H1N1 influenza A virus particles (orange) budding from lung cells. AMED-funded researchers have found that influenza A viruses with reduced susceptibility to baloxavir acid (BXA), the active form of the antiviral drug baloxavir marboxil, are just as pathogenic and transmissible as those that are susceptible to BXA.

© SCIENCE PHOTO LIBRARY

Influenza A viruses that are resistant to a new antiviral drug show no signs of being less active or transmissible than their non-resistant counterparts. This raises the spectre of the proliferation of antiviral-resistant strains of influenza A, unless multipronged strategies are employed.

The antiviral drug baloxavir marboxil (BXM) was approved for use in the USA and Japan in 2018. Unlike other antiviral drugs, BXM targets the polymerase acidic (PA) protein of influenza A and B viruses. However, influenza virus stains have been found that have reduced susceptibly to baloxavir acid (BXA), the active form of BXM, because they have a mutation in their PA gene. It was unclear how this mutation affects these mutant viruses’ pathogenicity and ability to spread.

Now, an AMED-funded study led by Yoshihiro Kawaoka and Masaki Imai, both of the University of Tokyo, has found that viruses with this mutation have similar pathogenicity and transmissibility as those without it.

The team isolated influenza A viruses with the mutation from patients in Japan and found that they grew just as well in cell culture as viruses lacking the mutation. The viruses also exhibited similar replicative abilities and pathogenicity in hamsters. Furthermore, they transmitted efficiently between ferrets via respiratory droplets.

These findings imply that the viruses with reduced susceptibility to BXA will not be at any significant disadvantage compared to BXA-susceptible viruses. “These findings suggest that the currently circulating seasonal influenza A viruses could maintain their viral fitness even though they have evolved to be less susceptible to BXA,” says Kawaoka. Combination treatments with multiple antiviral drugs may be needed.

Project: Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets

Researcher: Yoshihiro Kawaoka

Host Institution: University of Tokyo

AMED Funding: Leading Advanced Projects for medical innovation (LEAP), Japan Initiative for Global Research Network on Infectious Diseases (J-GRID), Research Program on Emerging and Re-emerging Infectious Diseases

Overcoming the final hurdle to bringing an eye treatment to patients

A procedure for repairing damage to the eyes is close to being cleared for use in Japan

A regenerative medicine technique that involves transplanting cultivated mouth cells onto damaged corneas is close to being approved for use in Japan.

© CNRI/SCIENCE PHOTO LIBRARY

Chie Sotozono of Kyoto Prefectural University of Medicine and her team really wanted patients to benefit from a procedure they had developed for regenerating damaged corneas. Since the eye conditions are relatively rare, it proved to be very challenging to find a pharmaceutical company willing to invest in the procedure. Instead, she opted to conduct an investigator-initiated clinical trial herself with all the challenges that involved. But before she could embark on the trial, she had to secure the needed funding.

That funding, along with other sources of support, came from AMED. The grant enabled Sotozono’s team to conduct a trial on seven patients. She says the results have been very encouraging, and she hopes the treatment will be approved by Japan’s Pharmaceuticals and Medical Devices Agency this fiscal year.

“Without AMED support, both financial and in other ways, we wouldn’t have been able to get this far,” says Sotozono.

The treatment, known as cultivated oral mucosal epithelial sheet transplantation (COMET), is for treating severe ocular-surface diseases. It involves taking cells from a person’s mouth, growing them in the lab and transplanting sheets of the cultivated cells onto the surface of the eye. COMET is unique in that both the mouth cells and the amniotic membrane they are cultivated on are grafted onto the patient’s eye. The membrane supplements loss of the existing membrane and its flexibility allows it to readily conform to the eye’s curved surface.

Project: Project Promoting Clinical Trials for Development of New Drugs

Researcher: Chie Sotozono

Host Institution: Kyoto Prefectural University of Medicine

AMED Funding: Project Promoting Clinical Trials for Development of New Drugs


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