Pediatrics Bonkowsky Lab
Our Projects & Funding
Current Research Projects
Project 1: Hypoxic disruption of CNS development
Hypoxic injury to the developing human brain causes life-long intellectual and behavioral deficits. These serious outcomes include autism spectrum disorders, cerebral palsy, depression, epilepsy, and intellectual disabilities. Currently there are no treatments to protect against the effects of prematurity and chronic hypoxic injury to the central nervous system (CNS). The ultimate goal of our research is to understand the fundamental molecular and neurobiological mechanisms by which hypoxia disrupts connectivity.
Recently, our lab developed a novel zebrafish system to examine the effects of hypoxia. Zebrafish's unique advantage is that it combines vertebrate CNS structures and genes with rapidity and efficiency for testing basic mechanisms. We use a combination of novel transgenic lines and innovative chemical and imaging approaches. Elucidation of these mechanisms offers the potential for designing effective and targeted therapeutic approaches.
Project 2: Connectivity Labeling
Specific visualization and manipulation of neural circuitry has remained a vexing problem in neurobiology. Classical methods rely upon analysis in fixed tissue, preventing characterization of function or behavior. Newer methods allow genetic targeting to specific neuron types and even identify single neurons, but synaptic partners and functional circuits are not accessible by these current methods. A more general related issue is how to induce expression of a transgene in a vertebrate system when two cells make contact. A solution to these issues could have wide applicability, both for experimental studies, as well as for potentially a variety of therapeutic options.
This project develops novel strategies to analyze vertebrate circuit construction and function. It includes the first genetic method for visualizing and driving expression in two cells that make contact, and offers the potential to identify and manipulate neuronal circuits in a vertebrate organism; the application of FingRs in vivo to analyze synapses; and a broad range of transgenic lines to look at different axon tracts.
Project 3: Leukodystrophies
Inherited leukodystrophies are diseases of the myelin, including abnormal myelin development, hypomyelination, or degeneration of myelin. The incidence of leukodystrophies is almost 1 in 7500 live births. Typical disease presentation occurs in the first three years of life with a 34% risk of death by age 8 years (Bonkowsky et al., 2010).
We have developed zebrafish models for leukodystrophies to use for drug screening and to characterize the fundamental disease mechanisms of leukodystrophies. We are using CRISPR knock-out and knock-in technologies; transgenic reporter lines; and motor behavior measurements.
We are currently studying X-linked Adrenoleukodystrophy (ALD); Vanishing White Matter Disease (VWMD); and Metachromatic Leukodystrophy (MLD); and are developing other models.
Project 1: Western Leukodystrophy Project
Genetic white matter disorders (leukodystrophies) have an incidence of 1:7500 live births. Our work aims to characterize the clinical history of leukodystrophies, and to develop novel therapies.
We are partnering with ALD Connect, funded through PCORI, to improve care and understanding of X-linked adrenoleukodystrophy and adrenomyeloneuropathy.
Project 2: Neuroprotective Roles for Magnesium
Preterm birth and hypoxic injury to the developing brain are associated with adverse neurodevelopmental outcomes including autism spectrum disorders, epilepsy, and intellectual disabilities. We are examining clinical outcomes as related to a potential neuroprotective role for magnesium in premature infants.
- NIH Director's New Innovator Award
- The March of Dimes Foundation
- Primary Children's Foundation
- Vanishing White Matter Foundation