Pilot Project Award |Overview
The Pilot Project award is given to a Boston Children’s Hospital faculty member to support new high-risk/high-yield projects that require the development of preliminary data or proof of concept studies in order to attract longer-term funding from theNational Institutes of Healthand other mainstream funding agencies.
2021 Pilot Project Awardees
Darius Ebrahimi-Fakhari, MD, PhD
and Mustafa Sahin, MD, PhD
Project title: Functional genomic screen in neuronal model of hereditary spastic paraplegia
Hereditary spastic paraplegia (HSP) is the most common cause of inherited spasticity and associated disability worldwide. Loss-of-function variants in the genes encoding the adaptor protein complex 4 (AP-4) lead to an ultrarare but prototypical form of HSP in children and can serve as a genetic model to understand the contributions of defective protein trafficking and autophagy to neurodegeneration. This project aims to use CRISPR-Cas9 and a unique human neuronal model of AP-4 deficiency to screen the effects of knockout of 8500 genes known to represent potential drug targets. The goal is to identify and characterize novel modulators of protein trafficking for the treatment of HSP.
Olaf Bodamer, MD, PhD
and Youngsook Lucy Jung, PhD
Project title: Characterizing chromatin modification in Kabuki syndrome
Kabuki Syndrome (KS) is a rare childhood disorder that affects multiple body systems and presents with a distinct physical appearance including a unique facial appearance, short stature, and skeletal abnormalities. It affects approximately 1 in 32,000 births and is incurable. The symptoms of KS vary widely and may include intellectual disability, weak muscle tone, hearing loss, and malformations of the heart, kidney, and gastrointestinal system, requiring care from many different health care specialists. KS is caused by genetic changes in one of two genes, KMT2D or KDM6A. Genes are regulated by their accessibility to binding factors, which may differ between tissue types and time points. This is achieved by packaging of genomic DNA into chromatin. Both KMT2D and KDM6A play crucial roles in this process. The aim of this project is to characterize chromatin changes driving KS using different tissue types of a mouse model and to examine the effects of these chromatin changes on organ development. The findings and datasets generated during this project will enable a better understanding of the disease mechanisms and help in the search for novel treatments for KS. Furthermore, the analysis framework can be applied to other rare childhood diseases.
2020 Pilot Project Awardees
Heather Olson, MD, MS
Project title: Genetic variants in inflammatory epilepsy: Rasmussen Encephalitis and FIRES
Rasmussen Encephalitis (RE) and Febrile Infection Epilepsy Syndrome (FIRES) are two rare devastating disorders that occur in children resulting in a severe seizure disorder not responding to medications along with additional neurological deficits. Additional deficits may include learning and behavioral problems, muscle weakness, and swallowing or vision difficulties for example. The underlying cause for these disorders is unknown. This pilot study seeks to investigate underlying genetic causes for these two rare and severe disorders with inflammatory components. Understanding the underlying biology could lead to better treatments in the future.
Amy O'Connell, MD, PhD
Project title: T Cell Receptor Repertoire Sequencing Enhances Specificity of Newborn Screening for SCID in Premature Infants
Infants born prematurely have abnormal development of several organ systems, leading to orphan diseases of the eyes (retinopathy of prematurity), lungs (chronic lung disease), and other systems. Our research has shown that some premature infants may also develop a disease of their immune system, specifically impacting the development of their T cells. Some former premature babies have low numbers of T cells, but it’s hard to know if the function of the T cells is impaired because the traditional tests are not accurate in premature infants. For this pilot study, we will use a technique that assesses how many diverse T cell receptors are in a blood sample from these infants. If T cells are functioning normally, there will be a diverse set/repertoire of these receptors. This will help us to determine whether some premature infants have abnormal T cell development due to their prematurity. It may also improve newborn screening for another orphan disease,severe combined immunodeficiency(SCID), by giving us an easier way to check T cell activity during prematurity, as traditional tests often give false-positive results in premature infants.
Anne O'Donnell-Luria, MD, PhD
Project title: Investigating the contribution of non-coding genetic changes to unsolved cases
Despite improvements in our ability to read the human genome, our understanding of how changes in the genome impact human disease remains limited. For example, although we know that disease-causing genetic changes can be located throughout the genome, current genetic testing is largely limited to only 1% of the human genome, which is the portion that codes for proteins. By contrast, genetic changes in the other 99% of the genome that alter when and where these proteins are produced are routinely ignored during genetic testing due to our poor ability to interpret their functional impact. This limitation hampers our ability to diagnose and provide targeted therapies for our patients. In this proposal, we aim to improve the diagnosis of patients with rare disorders by leveraging a novel method that determines whether a genetic change alters when and where a protein is produced, thereby enabling the interpretation of genetic variants in the other 99% of the genome. We aim to evaluate nine cases that have been enrolled through the Manton Center using this approach to help identify any genetic alterations underlying their disease.
This page was last updated on November 23, 2021.