Four scientists at the Herman B Wells Center for Pediatric Research received Translational Awards from the center to help fund their promising projects.
Impact of tau-mediated acute brain injury on long-term neurocognitive impairment in severe malaria
Dibya Datta, PhD, assistant research professor of pediatrics and member of the Infectious Diseases and Global Health research group at the Wells Center, was awarded for her project titled, “Impact of tau-mediated acute brain injury on long-term neurocognitive impairment in severe malaria.”
Project summary: Among the children who survive an episode of cerebral malaria, many are left with neurocognitive impairments for up to two years after they recover from the debilitating disease. Earlier this year, Datta published a study in which she and her team demonstrated that the protein tau, a marker of brain axonal injury, is above normal levels in the cerebrospinal fluid (CSF) of these children and is associated with long-term neurocognitive impairments.
However, identifying instances of brain injury in severe malaria using CSF biomarkers requires invasive lumbar punctures and is not a practical option for assessing acute brain injury and impairment in children. Datta will use her award to explore a more accessible blood-based source of tau as a biomarker for acute brain injury. She said that her team is particularly interested in the broad implications of the role of plasma tau as a marker of acute brain injury, such as identifying ways to prevent such injury, and developing focused rehabilitation for those identified at highest risk of long-term neurocognitive impairment.
Impact of GPR17 human variants on gut incretin secretion
Hongxia Ren, PhD, assistant professor of pediatrics and member of the Diabetes research group at the Wells Center, will use her award to help fund her project, “Impact of GPR17 human variants on gut incretin secretion.”
Project summary: Societal and lifestyle changes in the last few decades have led more instances of obesity among pediatric patients than ever before. Pediatric obesity is associated with increased risk for health issues later in life—such as adult obesity and associated health complications, decreased quality of life and lower life-expectancy. Conventional treatments for adult obesity have limitations, and there is a critical need to identify safe and effective pharmacological therapeutics to prevent and treat obesity in pediatric and adult patients.
Ren’s lab has worked to identify mechanisms of metabolic regulation, specifically a protein receptor called Gpr17. Her lab found that knocking this receptor out in animal models increased satiety (the “full” feeling) and improved glucose metabolism. Now, they’ve begun to examine variants of Gpr17 in humans and will use funds from this award to determine the impact of those variants on metabolic homeostasis.
Targeting the in-vivo adaptive response induced by inhibition of RAS/PI3K hyperactivation in Wilms tumor xenografts
M. Reza Saadatzadeh, PhD, assistant research professor of pediatrics and member of the Molecular Oncology and Experimental Therapeutics research group, was awarded to pursue his project titled, “Targeting the in-vivo adaptive response induced by inhibition of RAS/PI3K hyperactivation in Wilms tumor xenografts.”
Project Summary: Wilms tumor is the most common type of childhood kidney cancer and accounts for nearly 6% of all pediatric cancers. There is a critical need to develop therapies that can combat recurrent metastatic instances of Wilms tumor. Saadatzadeh’s project seeks to use new animal models of human Wilms tumor to study alterations and hyperactivation of signaling pathways, specifically the KRAS and PIK3CA signaling pathways, which play a central role in recurrent metastatic Wilms tumor.
Proteomic approaches will be used to discover small molecule inhibitor-induced adaptive response networks that may be directly or indirectly actionable. These data will aid in the prioritization of multi-targeted therapy for future in-vivo efficacy and safety studies that have the potential to improve outcomes in pediatric patients with metastatic Wilm’s Tumor.
The Role of FOXP3 ΔE2 isoform in asthma severity
Baohua Zhou, PhD, associate professor of pediatrics and associate professor of microbiology and immunology, is a member of the Pulmonary Inflammation, Asthma and Allergy research group at the Wells Center. He received the award for his project titled, “The Role of FOXP3 ΔE2 isoform in asthma severity.”
Project Summary: The transcription factor FOXP3 is key for the development and function of regulatory T cells that are critical to the suppression of asthma and allergy. The human FOXP3 gene expresses two forms of protein, called FOXP3 FL and FOXP3 ΔE2. Currently, the roles of these two proteins in health and disease have not been clearly defined.
Zhou’s team has developed a mouse strain to study the function of human FOXP3 forms. They found that mice expressing the human FOXP3 ΔE2 form develop more severe asthma-like disease, suggesting the expression of FOXP3 forms in humans may also contribute to asthma development and/or severity.
In this project, Zhou and his team will collaborate with physicians at the Riley Hospital for Children at IU Health to collect blood samples from patients with asthma. They’ll use these samples to directly study the relationship between FOXP3 ΔE2 expression and disease severity and to determine how the inflammatory environment seen in patients impacts the expression FOXP3 forms.
Zhou said that he hopes that this and future projects will help lead to the development novel strategies to treat and even prevent asthma by targeting the different FOXP3 protein forms.
The Herman B Wells Center for Pediatric Research was established in 1991 and is a component of the Department of Pediatrics. Today, it houses nearly 200 faculty, staff and trainees in eight thematic research groups that investigate the mechanisms of common and pervasive childhood illnesses such as asthma, diabetes and congenital heart defects and the rarest and most difficult-to-treat cancers and genetic syndromes.
