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keywords
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Extracellular Matrix, Proteoglycans, Pediatric Neurodegeneration, Perinatal brain injury, Neuroglia,
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overview
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Our research aims to understand the function of proteoglycans during brain and cartilage development. In collaboration with Dr. Schwartz, we have studied several proteoglycan mutant models which indicate that the proteoglycan aggrecan plays a key role in establishing appropriate gradients of growth factors during cartilage development and that it is involved as instructive signaling that controls astrocyte differentiation during avian brain development. More recently, we have developed a novel embryonic model for brain injury in the avian which allows analysis of glial precursor response to injury and modifications of matrix biosynthesis. This work led us to develop a novel multifactorial model of perinatal injury in mice in which we demonstrated that perinatal brain injury followed by exposure to lipopolysaccharide (as an analog of remote pathogen exposure), particularly affects maturation markers in oligodendrocytes, initiates a neuroinflammatory process and activates a neural stem cell response. These models will aid in our understanding of complex human diseases such as periventricular leukomalacia and cerebral palsy.
Another line of research aims to understand the involvement of astrocytes and microglia and the integrity of blood-CSF and the blood brain barrier in a mouse model of a Neuronal Ceroid Lipofuscinoses (NCLs, also known as Batten disease). NCLs are among the most common neurodegenerative diseases in the pediatric population, with an incidence estimated at 2-4 per 100,000 live births. Different forms of the diseases were originally classified based on the time of onset: infantile, late infantile (LINCL), juvenile and adult. Over 13 gene mutations have been found to be linked to NCLs. In particular, the classical late-infantile NCL (cLINCL) in humans is caused by mutations in the CLN2/TPP1 gene. The mouse model lacks expression of TPP1 and develops a lethal neurodegeneration in the first 5 month of life. We have addressed the evolution of the disease using RNAseq and have identified inflammation pathways in which microglia and astrocyte activation potentiate neuronal dysfunction, possibly by oxidative stress and damage of the blood–brain barrier integrity. Our long-term goal is to establish novel parameters for early disease detection which may lead to novel therapies.
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Domowicz, Miriam