This issue includes updates on CRI activities, as well as the first in what will be a regularly occurring focus on a pediatric researcher, highlighting the many connections we have throughout the university to build upon in our Children’s Research Institute (CRI).

Activities Update: On June 2, we shared our CRI vision and needs for financial support at the UNC Children’s Board of Visitors Meeting. By working closely with the UNC Medical Foundation, who hosted this event, we were able to bring awareness about why funding is crucial in our mission to: promote research collaborations, build infrastructure, and retain and recruit new faculty. To drive the point home on why research is needed, we discussed the link between research and treating patients. We also highlighted the recent addition of the Gene Therapy Center (GTC) to the Department of Pediatrics.

The Board of Visitors have close ties to our community and care deeply about our Children’s Hospital; several members have had a child in dire need at our hospital and unfortunately, some have lost a child here. These parents are a dedicated group who want their child’s memory to live on and want to give back to the hospital who worked hard for their child. One member has since made a pledge and several members have reached out to their communities with our message, which led to a pledged donation.

On May 25 we saw the submission of a collaborative T32 with Duke University titled: Unified Program for Therapeutics in Children (UPTiC). This new T32 application, lead and written by Ian Davis at UNC and Sallie Permar at Duke, aims to develop a comprehensive program to rigorously train pediatric physician-scientists in the development and testing of therapeutics by creating a strong cross-institutional mentorship network for pediatrician-scientists and providing a broad range of training opportunities. We are excited to be part of this collaborative submission that addresses a need specific to children. As stated in the submission “Over half of the pharmacological treatments used in hospitalized children are off-label. Further, most pediatric indications are rare, therefore limiting investment in drug discovery by pharma and emphasizing the importance of academic-led preclinical and clinical development. . . children are often referred to as “therapeutic orphans” and do not share the same benefits of the novel therapeutics pipeline as adults.” The NIH review is expected to take place this fall. Also, the DOP will be updating the processes to maintain data needed for T32 tables in order to facilitate the assembly of the immense information required for these submissions.

Mary Ellen Jones Renovation Update: The latest update on the Mary Ellen Jones building can be found here: http://news.unchealthcare.org/som-vital-signs/attachments/2016/mej-newsletter-july

Research focus of the month: To continue to inform each other of the research interactions in pediatrics, and in the spirit of the CRI mission to promote collaboration, we will highlight a different pediatric investigator’s collaborative efforts each month.

Ian Davis, MD, PhD

Because of the recently submitted T32, Ian Davis seemed a logical choice. Blending wet bench experimentation and computational analytics, the Davis lab applies genome-wide (genomic) strategies to explore the biological mechanisms that govern epigenetics and gene regulation. The lab applies this knowledge to develop new therapies and diagnostics for childhood diseases. A major focus of the Davis lab has been Ewing sarcoma, a tumor of children and young adults. The lab has demonstrated that the chromosomal rearrangement critical for Ewing sarcoma generates a transcriptional regulator that works by altering chromatin structure and that this role is dependent on a unique epigenetic state found in bone marrow-derived stem cells.

Collaborations across the UNC campus have been central for Dr. Davis’ research. His work with Stephen Frye, PhD and Samantha Pattenden, PhD in the Center for Chemical Biology and Drug Discovery in the Eshelman School of Pharmacy led to the adaptation of an assay for epigenetic state enabling the screening of an epigenetically targeted small molecule library for compounds that reverse accessible chromatin in disease-specific regions of Ewing sarcoma. Through this screen they were able to identify a specific class of compounds with therapeutic potential and identified a new compound that they are currently exploring. In a related collaboration with Dr. Pattenden and Paul Dayton, PhD, Biomedical Engineering, the Davis lab is exploring the examination of archival pathology specimens to identify epigenetic signatures.

As part of a long-standing collaboration with Brian Strahl, PhD, in Biochemistry and Biophysics, and Kim Rathmell, MD, PhD, formerly in the Department of Medicine and currently Division Chief of Medical Oncology at Vanderbilt University, the Davis lab has been studying a histone methyltransferase enzyme called SETD2. The gene for SETD2 is recurrently mutated in a significant percentage of renal cell carcinomas. They have shown that mutations in SETD2 lead to inappropriate transcription, which might promote cancer initiation or progression. A recent publication from this collaboration reported that this transcription enzyme preserves the accuracy of transcription during nutrient stress in yeast. Without this enzyme, genome-wide bi-directional cryptic transcription was observed, suggesting that this enzyme is critical to maintain proper transcription of DNA to RNA.

The lab’s expertise in transcription and genomic analysis has led to additional collaborations outside the field of cancer. The Davis lab contributed computational expertise to a study of cardiac development led by Frank Conlon, PhD, Department Biology/Genetics, that explored why mutations in a cardiac transcription factor gene (TBX5) lead to congenital heart disease. The study found that TBX5 represses inappropriate gene programs that are incompatible with cardiac development and that TBX5 mutations correlate with septal defects.

For more information on Ian Davis’ research visit: https://www.med.unc.edu/pediatrics/specialties/hematology-oncology/research