Tag Archive for: Tarik Haydar

Brain illustration

Paving the way toward better understanding and treatment of neonatal brain injuries

Brain illustration

The Gallo Lab’s latest research finds reduced expression of Sirt2 in the white matter of premature human infants and characterizes its role in white matter of the brain in normal conditions and during hypoxia.

Changes in myelination due to diffuse white matter injury are a common consequence of premature birth and hypoxic-ischemic injury due to asphyxia of sick term-born newborns. Hypoxic damage during the neonatal period can lead to motor disabilities and cognitive deficits with long-term consequences, including cerebral palsy, intellectual disability or epilepsy, which are often due to cellular and functional abnormalities.

The Gallo Lab, within the Center for Neuroscience Research at Children’s National Hospital, is focused on studying postnatal neural development and the impact of injury and disease on development and regeneration of neurons and glia. Their latest research, published in Nature Communications, finds reduced expression of Sirt2 in the white matter of premature human infants (born earlier than 32 weeks of gestation) and characterizes its role in white matter of the brain in normal conditions as well as during hypoxia.

What it means

The lab previously identified Sirt1 as important for the proliferative regenerative response of oligodendrocyte progenitor cells in response to chronic neonatal hypoxia. This new study characterizes the function of Sirt2 and finds that it acts as a critical promoter of oligodendrocyte differentiation during both normal brain development and after hypoxia.

It’s likely this reduced expression of Sirt2 contributes to the arrest in oligodendrocyte maturation and myelination failure seen in extremely low gestational age neonates. Therefore, targeting Sirt2 may be an opportunity to capture the early and small window of opportunity for therapeutic intervention.

How this moves the field forward

Sirtuins have been shown to play crucial therapeutic roles in various diseases, including aging, neurodegenerative disorders, cardiovascular disease and cancer. Identifying Sirt2 as a major regulator of white matter development and recovery and increasing the understanding of its protein and genomic interactions opens new avenues for Sirt2 as a therapeutic target for white matter injury in premature babies.

Why we’re excited

Interestingly, the team found that overexpression of Sirt2 in oligodendrocyte progenitor cells, but not mature oligodendrocytes, restores oligodendrocyte populations after hypoxia through enhanced proliferation and protection from apoptosis. This is exciting because:

  • It tells us that Sirt2 expression is very important for the transition from progenitor to differentiated oligodendrocyte.
  • It’s the first report, to the team’s knowledge, of Sirt2 regulating cell survival of oligodendrocytes.

Read more in Nature Communications

zika virus

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

zika virus

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

  • Cerebral organoids, which illuminate how a neuron reacts to a viral infection
  • Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
  • Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

girl with down syndrome

Study finds delayed oligodendrocyte progenitor maturation in Down syndrome

girl with down syndrome

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development.

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development. Children’s National Hospital experts discovered delayed maturation in oligodendrocyte progenitors in DS. Oligodendrocytes produce the white matter which insulates neural pathways and ensures speedy electrical communication in the brain. The researchers identified these delays by measuring gene expression at key steps in cell development, according to a new study published in Frontiers in Cellular Neuroscience.

The findings further suggest that brain and spinal cord oligodendrocytes differ in their developmental trajectories and that “brain-like” oligodendrocyte progenitors were most different from control cells, indicating that oligodendrocytes in the brains of people with DS are not equally affected by the trisomy 21.

“This is one of the critical steps towards identifying the key stages and molecular players in the DS white matter deficits,” said Tarik Haydar, Ph.D., director of the Center for Neuroscience Research. “With this knowledge, and with further work in this direction, we envision future therapies that may improve nerve cell communication in the brains of people with Down syndrome.”

The hold-up in the field

The mechanisms that lead to the reduction of white matter in the brains of people with DS are unknown. To better understand early neural precursors, they used isogenic pluripotent stem cell lines derived from two individuals with Down syndrome to study the brain development and spinal cord oligodendrocytes.

“I was excited that we discovered another example of how important it is not to generalize when studying DS brain development,” said Haydar. “This is one of several papers, from our group and others, that demonstrate how important it is to be very specific about the brain area and the developmental stage when investigating the causes of DS brain dysfunction.”

What’s next

Dysmaturation of oligodendrocyte cells are a relatively new discovery by the Haydar Lab, one of the preeminent labs in DS research. These results isolate specific steps that are affected in human cells with trisomy 21. They are using these results to develop a drug screening platform that may prevent altered generation of oligodendrocytes in the future.

You can read the full study “Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21” in Frontiers in Cellular Neuroscience.

illustration of the brain

New research provides glimpse into landscape of the developing brain

illustration of the brain

Stem and progenitor cells exhibit diversity in early brain development that likely contributes to later neural complexity in the adult cerebral cortex, this according to a new study in Science Advances. This research expands on existing ideas about brain development, and could significantly impact the clinical care of neurodevelopmental diseases in the future.

Stem and progenitor cells exhibit diversity in early brain development that likely contributes to later neural complexity in the adult cerebral cortex, this according to a study published Nov. 6, 2020, in Science Advances. Researchers from the Center for Neuroscience Research (CNR) at Children’s National Hospital say this research expands on existing ideas about brain development, and could significantly impact the clinical care of neurodevelopmental diseases in the future. The study was done in collaboration with a research team at Yale University led by Nenad Sestan, M.D, Ph.D.

“Our study provides a new glimpse into the landscape of the developing brain. What we are seeing are new complex families of cells very early in development,” says Tarik Haydar, Ph.D., director of CNR at Children’s National, who led this study. “Understanding the role of these cells in forming the cerebral cortex is now possible in a way that wasn’t possible before.”

The cerebral cortex emerges early in development and is the seat of higher-order cognition, social behavior and motor control. While the rich neural diversity of the cerebral cortex and the brain in general is well-documented, how this variation arises is relatively poorly understood.

“We’ve shown in our previous work that neurons generated from different classes of cortical stem and progenitor cells have different functional properties,” says William Tyler, Ph.D., CNR research faculty member and co-first author of the study. “Part of the reason for doing this study was to go back and try to classify all the different progenitors that exist so that eventually we can figure out how each contributes to the diversity of neurons in the adult brain.”

Using a preclinical model, the researchers were able to identify numerous groups of cortical stem and precursor cells with distinct gene expression profiles. The team also found that these cells showed early signs of lineage diversification likely driven by transcriptional priming, a process by which a mother cell produces RNA for the sole purpose of passing it on to its daughter cells for later protein production.

Tarik Haydar

“Our study provides a new glimpse into the landscape of the developing brain. What we are seeing are new complex families of cells very early in development,” says Tarik Haydar, Ph.D., director of CNR at Children’s National, who led this study. “Understanding the role of these cells in forming the cerebral cortex is now possible in a way that wasn’t possible before.”

Using novel trajectory reconstruction methods, the team observed distinct developmental streams linking precursor cell types to particular excitatory neurons. After comparing the dataset of the preclinical model to a human cell database, notable similarities were found, such as the surprising cross-species presence of basal radial glial cells (bRGCs), an important type of progenitor cell previously thought to be found mainly in the primate brain.

“At a very high level, the study is important because we are directly testing a fundamental theory of brain development,” says Zhen Li, Ph.D., CNR research postdoctoral fellow and co-first author of the study. The results add support to the protomap theory, which posits that early stem and progenitor diversity paves the way for later neuronal diversity and cortical complexity. Furthermore, the results also hold exciting translational potential.

“There is evidence showing that neurodevelopmental diseases affect different populations of the neural stem cells differently,” says Dr. Li. “If we can have a better understanding of the complexity of these neural stem cells there is huge implication of disease prevention and treatment in the future.”

“If we can understand how this early landscape is affected in disorders, we can predict the resulting changes to the cortical architecture and then very narrowly define ways that groups of cells behave in these disorders,” adds Dr. Haydar. “If we can understand how the cortex normally achieves its complex architecture, then we have key entry points into improving the clinical course of a given disorder and improving quality of life.”

Future topics the researchers hope to study include the effects of developmental changes on brain function, the origin and operational importance of bRGCs, and the activity, connections and cognitive features enabled by different families of neurons.

illustration of brain showing cerebellum

NIH grant supports research on locomotor dysfunction in Down Syndrome

illustration of brain showing cerebellum

The National Institutes of Health (NIH) has granted the Children’s National Research Institute (CNRI) nearly $500,000 to better understand and identify specific alterations in the circuitry of the cerebellum that results in locomotor dysfunction in down syndrome.

Down syndrome (DS), the most commonly diagnosed chromosomal condition, affects a range of behavioral domains in children including motor and cognitive function. Cerebellar pathology has been consistently observed in DS, and is thought to contribute to dysfunction in locomotor and adaptive motor skills. However, the specific neural pathways underlying locomotor learning that are disrupted in DS remain poorly understood.

The National Institutes of Health (NIH) has granted the Children’s National Research Institute (CNRI) nearly $500,000 through their NIH-wide initiative INCLUDE – INvestigating Co-occurring conditions across the Lifespan to Understand Down syndrome – to better understand and identify specific alterations in the circuitry of the cerebellum that results in locomotor dysfunction in DS. The INCLUDE initiative aims to support the most promising high risk-high reward basic science.

“There is still a lot unknown about Down syndrome, in particular how fundamental cellular and physiological mechanisms of neural circuit function are altered in this syndrome,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director of CNRI. “Grant funding is particularly important to have the resources to develop and apply new cutting-edge methodology to study this neurodevelopmental disorder.”

The main goal of this research is to identify specific alterations in the circuitry of the cerebellum that result in locomotor dysfunction in DS. Defining specific abnormalities in motor behavior, and identifying the brain regions and neurons which are functionally involved will provide the basis for developing potential therapies for treating motor problems in individuals with DS.

“The last decade has brought rapid advances in neurotechnology to address questions at the ‘systems-level’ understanding of brain function,” says Aaron Sathyanesan, Ph.D., a Children’s National postdoctoral research fellow. “This technology has rarely been applied to preclinical models of neurodevelopmental disorders, and even more rarely to models of Down syndrome.”

An example is the use of fiber-optics to probe changes in neural circuitry during behavior. Using this technology, researchers can now directly correlate the changes in circuitry to deficits in behavior.

“Along with the other approaches in our proposal, this represents the synthesis of a new experimental paradigm that we hope will push the field forward,” says Dr. Sathyanesan.

In 1960, the average life expectancy of a baby with Down syndrome was around 10 years. Today, that life expectancy has increased to more than 47 years. That significant increase reflects critical advances in medicine, however, kids with DS still live with long-term challenges in motor and cognitive ability.

Children’s National strongly supports translation and innovation, and recently recruited internationally renowned DS researcher, Tarik Haydar, Ph.D., as its new director of the Center for Neuroscience Research.

“We’re building significant strength in this area of research. This grant helps open new avenues of investigation to define which cells and circuits are impacted by this common neurodevelopmental disorder,” says Dr. Gallo. “Our cutting-edge approach will help us answer questions that we could not answer before.”