Pilot Project Award

The Pilot Project award is given to a Boston Children’s Hospital faculty member to support new high risk/high yield projects that require development of preliminary data or proof of concept studies in order to attract longer term funding from the National Institute of Health and other mainstream funding agencies. One-year research proposals for up to $50,000 (inclusive of overhead at the current philanthropic fund rate) will be considered with competitive renewal for a second year a possibility.


2018 Pilot Project Awards:

Boxun Zhao, PhD
Mentor: Alice Lee, PhD and Tim Yu, MD, PhD
Project title: Pathogenic structural variant identification and splicing defect correction

Dr. Zhao received his Ph.D. in Genetics in 2017 from Peking Union Medical College at Tsinghua University in Beijing, China. During his doctoral research, he studied somatic retrotransposon insertions in the human brain and neurological disorders. He joined the laboratory of Dr. E. Alice Lee in the Division of Genetics and Genomics at Boston Children's Hospital in August 2018 after a one-year postdoctoral training at the National Institute of Biological Sciences (NIBS), Beijing. His experience in human retrotransposons and training in both experimental and computational biology provides him a solid foundation to pursue his long-term goal of resolving the importance and impact of retrotransposons and other structural variants in human diseases and translating scientific discoveries into therapeutics. Advances in next-generation sequencing have revolutionized the diagnosis of genetic diseases; however, there remains a significant fraction of genetic diseases that are not linked to causal mutations, in part because it is challenging to study some structural variants with current sequencing technologies and conventional analytical pipelines. This points to an urgent need for specialized variant calling tools, as well as long-read or linked-read sequencing approaches to elucidate the full spectrum of genomic variants. We propose to undertake an investigation of structural variants as underexplored sources of DNA variation that likely underlie a large portion of unresolved genetic cases. We will systematically identify pathogenic structural variants and characterize their effects on gene transcripts. This research will advance our understanding of the importance of structural variants as a mechanism underlying orphan diseases and will facilitate the development of novel diagnoses and therapeutics.

 

Lucia Ambrosio, MD, PhD
Mentor: Anne Fulton, MD
Project title: Translational Read-Through Inducing Drugs (TRIDS) to treat Inherited Retinal Disorders (IRDs)

Dr. Lucia Ambrosio received her MD and PhD at University of Naples Federico II. Her graduate studies focused on the electrophysiological circuitry of the retina in age-related macular degeneration. In 2006, she joined the Residency Program in Ophthalmology at University of Naples Federico II. During these years, she published on the electrophysiological tests on the inherited retinal dystrophies and optic nerve diseases. In 2015 Dr. Ambrosio joined Dr. Anne Fulton’s Infant Vision Lab at Boston Children’s Hospital to start post-doctoral training. Her research focused on X-linked juvenile retinoschisis and was supported by a Knights Templar Eye Foundation Career-Starter grant. In the spring 2018 Dr. Ambrosio was promoted to Instructor in Ophthalmology at Harvard Medical School.

Currently, Dr. Ambrosio’s research centers on utilizing read-through therapy to identify compounds that may affect inherited retinal disorders (IRDs), each of which is an orphan disease. Read-through is a gene-based therapeutic approach for hereditary diseases caused by premature termination codon (PTCs) mutations, based on the discovery that small molecules, known as TRIDs (translational read-through inducing drugs), enable the translation machinery to suppress a nonsense codon and extend the nascent peptide chain; consequently, these molecules contribute in the full-length protein synthesis. In collaboration with BCH Translational Lab, Dr. Ambrosio plans to create patient-specific cell lines—from skin-derived fibroblasts and EBV-transformed lymphoblastoid cells from peripheral blood mononuclear cells—of patients with the rare syndromic ciliopathy, Bardet Biedl syndrome (BBS), as well as healthy controls. These banked specimens will be the cellular material to test several TRIDs she has selected. After treatment with TRIDs, mRNA, proteins, and a specific functional assay for markers for cilia will be evaluated. The results in BBS subjects and controls will be compared to demonstrate a successful read-through process as restoration of the proteins transcription.