MtDNA Gene Expression, Carousel Ball, NIH Innovator Awards, NKAP-related Syndrome, Discussing Youth Suicide

From identifying a new neurodevelopmental syndrome to novel discoveries about mitochondrial DNA, this week’s research roundup shows how Children’s Hospital of Philadelphia experts connect the dots to better understand disease origins. Also find out which early career investigators received New Innovator Awards from the National Institutes of Health. In recognition of World Mental Health Day, PolicyLab researchers discussed innovative approaches to suicide prevention in young adults. And a huge “thank you” goes to fundraisers at the annual Carousel Ball for their generous support of research and treatment at the Cardiac Center.

Subtle Mitochondrial DNA Mutations Alter Expression of Nuclear Genes

A game-changing publication describes a discovery 30 years in the making for Douglas Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. In a study published in the Proceedings of the National Academy of Sciences, a team of researchers led by Dr. Wallace identified the biological mechanisms by which mutations in mitochondrial DNA (mtDNA) alter energy flow and metabolism, creating signals that affect how genes are expressed within a cell nucleus.

While such changes in mtDNA are subtle, they may have big implications for a patient’s health: The team found that modest increases in heteroplasmy (when a cell contains a mix of normal and mutant DNA) can trigger shifts in both nuclear gene expression and clinical conditions.

“We previously showed that changes in mitochondrial DNA strongly regulate the expression of nuclear genes,” said Dr. Wallace in a press release. “Our new study reveals the molecular basis of this process, connecting the dots between mtDNA mutations and their effects on human health. Ultimately, we aim to use this increased understanding to guide us to effective treatments for mitochondrial diseases, and possibly for other complex disorders.”

The finding helps to explain why mitochondrial disorders are so complex and suggests that relatively small therapeutic changes in mitochondrial energetics could benefit patients who currently have few options for treatment. Dr. Wallace conducted the research in collaboration with scientists from CHOP, the University of Pennsylvania, and Drexel University.

Read more in the press release.

2019 Carousel Ball Raises $3.5 Million for Cardiac Center

Since its inception in 1957, the Carousel Ball has celebrated discoveries in pediatric medicine made at CHOP and the community of supporters who raise funds for our research breakthroughs. This year’s black-tie event, held Oct.12 and sponsored by Wawa, raised a record-breaking $3.5 million for the Cardiac Center at CHOP. Almost 900 attendees gathered at the Met Philadelphia and celebrated this year’s event honorees, Richard D. Wood Jr. and the Wood family, who are the founding family of Wawa.

“It’s a night where we celebrate the power of philanthropy to support our mission of pushing the limits of possibility for today’s patients and advancing life-changing research to create a better tomorrow,” said Madeline Bell, President and CEO of CHOP, in a press release.

With the funds raised from the record-breaking event, researchers and clinicians at the Cardiac Center will continue to advance and revolutionize treatments for children with heart disease.

“On behalf of the Cardiac Center, I’d like to thank all of the Carousel Ball sponsors, co-chairs, committee members, and the Wood family,” said Jonathan Chen, MD, chief of the Division of Cardiothoracic Surgery and co-director of the Cardiac Center. “Through their commitment and generosity, they all help play a role in what is next for the Cardiac Center – innovative treatments, groundbreaking research, and ultimately better outcomes for patients affected by heart disease.”

Read more in the press release.

NIH Awards High-Risk, High-Reward Grants to Early Career CHOP Researchers

The National Institutes of Health recognized two CHOP researchers with the , a highly competitive grant that will advance each scientist’s cutting-edge research in biomedicine. Each of the grants total $1.5 million over a five-year period and support innovative research by early career investigators under the NIH Common Fund’s broader High-Risk, High Rewards Program.

Join us in congratulating William Peranteau, MD, an investigator at CHOP’s Center for Fetal Research and Ophir Shalem, PhD, of CHOP’s Raymond G. Perelman Center for Cellular and Molecular Therapeutics. Both Drs. Peranteau and Shalem enlist CRISPR, a powerful gene-editing tool, in their research, focusing on prenatal gene editing and the development of functional genomics tools for protein function, respectively.

Dr. Peranteau’s grant project, “In Utero CRISPR-mediated Gene Editing to Cure Monogenic Disorders,” investigates the use of CRISPR gene editing to cure or reduce the severity of genetic disorders before birth. Meanwhile, Dr. Shalem’s grant project, “Direct and Rapid Control of Proteins at Scale,” aims to develop and apply functional genomics tools to study protein function by direct, large-scale perturbations.

Read more in the press release.

Genetics Researchers Identify New Neurodevelopmental Syndrome

In collaboration with researchers from eight other countries, scientists at CHOP identified a mutation in the NKAP gene that causes developmental delay, intellectual disability, behavioral abnormalities, and musculoskeletal problems in children. Discovery of the newly diagnosed condition, named NKAP-related syndrome, will allow clinicians to give clear diagnoses to patients who share the syndrome’s phenotype and mutation, and help build the foundation for developing future treatments.

“The function of NKAP in our bodies has been poorly understood,” said Kosuke Izumi, MD, PhD, study leader and a clinical geneticist and genetics researcher at CHOP. “We discovered novel functions in brain and musculoskeletal development. Furthermore, we have started a patient registry to collect clinical information on patients with this rare diagnosis. Identifying more patients may help to reveal the full spectrum of medical issues seen in NKAP-related syndrome.”

In the paper published Oct. 3 in the American Journal of Human Genetics, Dr. Izumi and his colleagues describe their study of 10 children and young adults who exhibit developmental delay, intellectual disability, and behavioral problems, as well as tall stature, scoliosis, and joint conditions. Through exome sequencing, the team successfully identified NKAP gene mutations on the X chromosome. The team also showed that the mutation appeared to “dial down” the gene’s effects on RNA and proteins – a finding also revealed in zebrafish models with an analogous mutated gene.

Learn more in the press release.

New PolicyLab Q&A Discusses Expanding Research to Address Suicide

In light of World Mental Health Day earlier this month, a new Q&A with Rhonda Boyd, PhD, PolicyLab researcher, explores current trends in youth suicide and ongoing research to help children and teens at risk. In her role as associate director of CHOP’s Child and Adolescent Mood Program in the outpatient clinic of the Department of Child and Adolescent Psychiatry and Behavioral Sciences, Dr. Boyd specializes in evaluating and treating youth with depression.

Dr. Boyd discusses multiple factors that may underlie an increasing trend in youth suicide, explains why suicide prevention is unique in youth and adolescents, and highlights the gaps in knowledge that researchers must address to make a change.

“Identification of risk and development of evidence-based treatments that are gender, age, and culturally responsive will allow us to make strides in fostering mental health among youth,” said Dr. Boyd in the Q&A.

Read the full Q&A on PolicyLab’s website.

ICYMI

Catch up on our headlines from our Oct. 4 In the News:

• Most Widely Used Screening Tool for Autism Spectrum Disorder: Is it Accurate?
• ECMO Center Manager Awarded Prestigious Fellowship
• Generous Gift Enables CHOP to Expand Palliative Care Program
• New Research Leadership Role for Physician Scientist Brian Fisher
• Study Finds Slower Responses to Sounds by Nonverbal Children with Autism

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