Kazue Hashimoto-Torii Archives

Caspases may link brain cell degeneration and cardiac surgery

April 29, 2022

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

A review article in the journal Cell Press: Trends in Neuroscience outlines the wide variety of cellular signaling roles for caspase proteins — a type of cellular enzyme best known for its documented role in the natural process of cell death (apoptosis). The authors, including Nemanja Saric, Ph.D., Kazue Hashimoto-Torii, Ph.D., and Nobuyuki Ishibashi, M.D., all from Children’s National Research Institute, pay particular attention to what the scientific literature shows about caspases’ non-apoptotic roles in the neurons specifically. They also highlight research showing how, when activated during a cardiac surgery with anesthesia and cardiopulmonary bypass, these enzymes may contribute to the degeneration of brain cells seen in young children who undergo heart surgery for critical congenital heart defects (CHDs).

Why it matters

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

The authors propose that these non-apoptotic activities of caspases may be behind some of the adverse effects on the developing brain related to cardiac surgery and anesthesia. Those adverse effects are known to increase risk of behavioral impairments in children with congenital heart disease who underwent cardiac surgery with both anesthesia and cardiopulmonary bypass at a very young age.

This work is the first to propose a possible link between developmental anesthesia neurotoxicity and caspase-dependent cellular responses.

The patient benefit

Better understanding of the time and dose-dependent effects of general anesthetics on the developing brain, particularly in children who have genetic predispositions to conditions such as CHDs, will help researchers understand their role (if any) in behavioral problems often encountered by these patients after surgery.

If found to be a contributing factor, perhaps new therapies to mitigate this caspase activity might be explored to alleviate some of these adverse effects on the developing brain.

What’s next?

The authors hope to stimulate more in-depth research into caspase signaling events, particularly related to how these signaling events change when an anesthetic is introduced. Deeper understanding of how anesthetics impact caspase activation in the developing brain will allow for better assessments of the risk for children who need major surgery early in life.

Children’s National leads the way

Children’s National Hospital leads studies funded by the U.S. Department of Defense to better understand how these other roles of caspases, which until now have not been well-documented, may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

Multidisciplinary team seeks to reverse epigenetic changes associated with fetal alcohol syndrome disorder

January 21, 2022

The team hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

A clinical team joined forces with a research team at Children’s National Hospital to help advance treatments that can improve a child’s development caused by fetal alcohol syndrome disorder (FASDs), which is a group of conditions that can occur in a person who was exposed to alcohol before birth. This boost in collaboration between the bench and clinical hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

So far, Children’s National experts have published various pre-clinical studies that identified epigenetic changes caused by alcohol exposure during pregnancy. These changes observed in the pre-clinical models created neuropsychiatric problems like patients with fetal alcohol syndrome disorder. Now, they want to bring such potential treatments effective in pre-clinical models to the bedside.

“As a first step, we are going to test whether the epigenetic changes that were observed in pre-clinical models of FASD are also true in human patients,” said Kazue Hashimoto-Torii, Ph.D., principal investigator of the Center for Neuroscience Research at Children’s National. “We hope a small amount of blood donated by patients with FASD reveal the changes. Meanwhile, my group has also been optimizing drug candidates that reverse the epigenetic changes toward clinical trials.”

Advances in genetics and genomics have led to discoveries about the timing of exposure and developmental outcomes and genetic and epigenetic signatures that may be protective or harmful in terms of how in utero alcohol exposure affects developmental outcomes.

The hold-up in the field

While the exact number of people with FASDs is unknown, the National Institutes of Health estimates that 1% to 5% of the population have FASDs. FASDs has a spectrum of diagnoses that represent a broad range of effects that can be manifested in an individual whose mother drank alcohol during pregnancy. These conditions can affect everyone in different ways and range from mild to severe. Individuals with mild conditions may go undiagnosed. The more affected individuals have comorbid attention-deficit/hyperactivity disorder (ADHD) and behavioral problems that become the focus of clinical encounters. The individual’s health care provider may not recognize the core features as part of FASD.

“Because there is a stigma associated with drinking while pregnant, many providers fail to get this history, and women may be reluctant to offer this information,” said Andrea Gropman, M.D., division chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National. “There are subtle and more obvious facial dysmorphology that may help with suspicion or identification, but many individuals do not have these findings.”

The core features may be nonspecific, such as intellectual disabilities and problems with behavior and learning, difficulties with math, memory, attention, judgment and poor impulse control, which are frequent findings in ADHD, autism, learning disorders and other conditions.

“Unless history is taken and FASD is in the differential diagnosis, the diagnosis may not be made,” said Dr. Gropman. “Individuals with FASD may feel stigmatized and opt not to participate in clinical trials.”

As mentioned by Dr. Gropman, stigma can make a patient family be reluctant to seek treatment, and thus the development of treatment for FASD cannot make significant progress to date, Hashimoto-Torii added.

Children’s National Hospital leads the way in an IRB approved study

Researchers at Children’s National have identified a potential drug candidate that reverse the epigenetic changes and may lead to clinical trials. The team is seeking people to participate in an IRB approved study. The study will involve cognitive testing, filling out surveys about current functioning and cheek swab and blood sample to determine if these changes are seen in patients. To participate, subjects must be

Children between the ages 5-12 with prenatal alcohol exposure.
Mother of child recruited above.

For participation, please contact Grace Johnson, research coordinator at to screen for eligibility at 202-476-6034 or gjohnson3@childrensnational.org

Meet the multidisciplinary team with different yet complementary skills in different fields, such as basic science, medical, social sciences, neurology and developmental disabilities, and development, who are working tirelessly to address the complex health problem.

Gropman lab:

Andrea Gropman, M.D., received her medical doctorate degree from the University of Massachusetts Medical School and specializes in neurogenetics, with a focus on mitochondrial disorders and Smith Magenis syndrome. Her latest research focuses on atypical patterns of inheritance, childhood mitochondrial disorders and other inborn errors of metabolism presenting with white matter disease.

Meira Meltzer, M.A., M.S., C.G.C., genetic counselor with a demonstrated history of working in the hospital and healthcare industry. Also skilled in molecular biology, clinical research and medical education. Strong healthcare services professional with a M.S. focused on genetic counseling from Brandeis University.

Cathy Scheiner, M.D., developmental behavioral pediatrician with a special interest in attention-deficit / hyperactivity disorder (ADHD), cerebral palsy and premature infant.

Grace Johnson, research assistant.

Hashimoto-Torii Lab:

Kazue Hashimoto-Torii, Ph.D., received her postdoctoral training in the Pasko Rakic laboratory at Yale University. Her research focuses on neurobehavior problems of children that stem from their environment during development, such as prenatal exposure to alcohol, drug and high-level glucose. A few drug candidates that her lab discovered have been patented and her lab is currently working hard to bring those medicines to bedside.

Satoshi Yamashita, M.D., Ph.D., postdoctoral research fellow skilled in developmental neurobiology. He is a pediatrician with Japanese medical license and received his Ph.D. with iPS cell research for STXBP1 encephalopathy in Japan.

Chiho Yamashita, B.N., research assistant passionate about child disease research. She is a nurse with a Japanese nursing license and worked in the pediatric department in Japan.

Primary cilia safeguard cortical neurons from environmental stress-induced dendritic degeneration

December 21, 2020

Fetus and neonates are under the risk of exposure to various external agents, such as alcohol and anesthetics taken by the mother. However, primary cilia can protect neurons by activating cilia-localized molecular signaling that inhibits degeneration of neuronal processes, according to the study’s findings.

A new study led by Kazue Hashimoto-Torii, Ph.D. and Masaaki Torii, Ph.D., both principal investigators for the Center for Neuroscience Research at Children’s National Hospital, found that primary cilia – tiny hair-like protrusions from the body of neuronal cells – protect neurons in the developing brain from adverse impacts of prenatal exposure.

Fetus and neonates are under the risk of exposure to various external agents, such as alcohol and anesthetics taken by the mother. However, primary cilia can protect neurons by activating cilia-localized molecular signaling that inhibits degeneration of neuronal processes, according to the study’s findings.

“Remarkably, the developing brain is equipped with intrinsic cell protection that helps to minimize the adverse impacts of to various external agents,” said Dr. Hashimoto-Torii. “However, the mechanisms of such protection have been unclear. Our study provides the first evidence that the tiny hair-like organelle protects neurons in the perinatal brain from adverse impacts of such external agents taken by the mother.”

The findings suggest that subtle alterations in primary cilia due to genetic conditions may lead to various neurodevelopmental disorders if combined with exposure to external agents from the environment. The findings also suggest that ciliopathy patients who have abnormal ciliary function due to genetic causes may have increased risk of abnormal brain development upon exposure to external agents.

“Clarifying diverse roles of cilia provides essential information for clinicians and patients with potential deficits in primary cilia to take extra precautions to avoid the risks for long-term negative impacts of external factors,” Dr. Torii explained. “We hope that further studies will define the whole picture of cilia-mediated neuroprotection and help us to advance our understanding of its importance in the pathogenesis of neurodevelopmental disorders.

This may ultimately lead to the development of treatment for various neurodevelopmental disorders,” he added.

The uniqueness of the study stems from the investigation of the role of cilia in brain development at the risk of exposure to various external factors that occur in the real world. Little is known about how the normal and abnormal brain development progresses in an environment where many external factors interact with intrinsic cellular mechanisms.

The study is a collaboration with researchers at Yale University and Keio University, Japan. Other Children’s National researchers who contributed to this study include Seiji Ishii, Ph.D.; Nobuyuki Ishibashi, M.D.; Toru Sasaki, M.D., Ph.D.; Shahid Mohammad, Ph.D.; Hye Hwang; Edwin Tomy; and Fahad Somaa.

U.S. DoD awards $2M for study to protect neurological function after cardiac surgery

July 2, 2020

A collaboration between clinical and basic science researchers including Drs. Ishibashi, Hashimoto-Torii, Jonas, and Deutsch, seeks to to understand how caspase enzyme activation plays a role in the development of fine and gross motor skills in children who underwent cardiac surgery for CHD repair.

The U.S. Department of Defense has awarded $2 million to Children’s National Hospital to study how a family of protease enzymes known as caspases may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

This U.S. Army Medical Research Acquisition Activity Award, Anesthesia Neurotoxicity in Congenital Heart Disease, is led by principal investigator Nobuyuki Ishibashi, M.D., with both clinical and basic science co-investigators including Kazue Hashimoto-Torii, Ph.D., (Neuroscience), Richard Jonas , M.D., (Cardiovascular Surgery) and Nina Deutsch, M.D., (Anesthesiology).

While the specific cellular and molecular mechanisms of how anesthesia and cardiac surgery impact cortical development are poorly understood, both seem to impact brain growth and development in young children. The most common neurologic deficit seen in children after CHD surgical repair is the impairment of fine and gross motor skills.

Both anesthetic agents and inflammation like that seen as a result of cardiopulmonary bypass have also been shown to contribute to the activation of a specific group of enzymes that play an essential role in the routine (programmed) death of cells: caspases. However, recent pre-clinical research shows that these enzymes may also contribute to other alterations to cells beyond cell death, including making changes to other cell structures. In pre-clinical models, these changes cause impairments to fine and gross motor skills – the same neurological deficits seen in children with CHD who have undergone procedures requiring prolonged anesthesia and cardiopulmonary bypass.

The research team hypothesizes that caspases are extensively activated as a result of cardiac surgery and while that activation is rarely causing reduced numbers of neurons, the changes that caspase enzymes trigger in neurons are contributing to neurological deficits seen in children with CHD after surgery.

While the study focuses specifically on the impacts of cardiac surgery for correction of a heart defect, the findings could have major implications for any pediatric surgical procedure requiring prolonged anesthesia and/or cardiopulmonary bypass.

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