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Gabriella D'Arcangelo
Gabriella D'Arcangelo
Professor and Vice Chair
...
(848) 445-2839
B323 Nelson Labs
Molecular mechanisms of mammalian brain development, injury, and neurological disorders

Biography

B.S. Biological Sciences, University of Bari, Italy
Ph.D., Neurobiology & Behavior, State University of New York at Stony Brook

Thomas Curran, advisor. The Roche Institute of Molecular Biology, Nutley, NJ, and
St. Jude Children’s Research Hospital, Memphis, TN.

Research Associate, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN.
Assistant Professor, Department of Pediatrics, Baylor College of Medicine, and Principal Investigator in the Gordon and Mary Cain Pediatric Neurology Research Foundation, Texas Children’s Hospital, Houston, TX.
Associate professor, Department of Cell Biology & Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ.

Major awards, honors, and professional activities:

  • Basil O'Connor Starter Scholar Research Award, The March of Dimes Birth Defects Foundation, 2000
  • Young Investigator Award, National Alliance for Research on Schizophrenia and Depression (NARSAD), 2002
  • Graduate Program in Neurobiology and Behavior, SUNY at Stony Brook, Distinguished Alumnus Award 2003
  • Essel Investigator Award, NARSAD, 2004
  • Citizens United for Research in Epilepsy (CURE), The Rhode Island Award, 2005
  • Julie’s Hope Award, CURE, 2007
  • NARSAD Independent Investigator Award, 2009
  • Standing Member of Developmental Brain Disorders (DBD) Study Section, Center for Scientific Review, NIH, 2009-2015
  • Teaching faculty in the Society for Neuroscience sponsored Neurobiology of Disease Workshop “Human Brain Malformations: From Genetics to Therapeutics”, Chicago, IL, 2015.
  • Guest Associate Editor for the Research Topic “Reelin-related neurological disorders and animal models”, Front Cell Neurosci, 2016
  • Idea Development Award, Department of Defense, Congressionally Directed Medical Research Programs, Tuberous Sclerosis Complex Research Program, 2016-2019
  • Faculty Award of Distinction, Rutgers, 2017

Current Research

Molecular mechanisms of mammalian brain development, injury, and neurological disorders
Neuroscience

Research Summary: My research focuses on molecular mechanisms that govern mammalian brain development, such as neurogenesis, neuronal migration, differentiation and synaptic connectivity. Abnormalities in these processes underlie cognitive dysfunction in developmental brain disorders and injury. Our short-term goal is to improve our mechanistic understanding of these diseases through experimental approaches that exploit genetically modified mouse models and human induced pluripotent stem cells (iPSC). The long-term goal of this work is to foster the development of new strategies for the treatment of neurological disorders and traumatic brain injury. Current projects include:

1. The function of Reelin in brain development and injury. Reelin is an extracellular protein that critically controls neuronal migration during embryonic brain development, and also promotes dendrite outgrowth, synapse formation, synaptic activity and plasticity during postnatal development and in the adult brain. Loss of REELIN function in humans cause a severe neurological disorder called lissencephaly with cerebellar hypoplasia, and mutations or polymorphisms in this gene are associated with cognitive dysfunctions such as schizophrenia and autism, as well as epilepsy. Using the Reelin mutant mouse reeler and conditional knock out mutants that are defective in Reelin signal transduction, we investigate the cellular and molecular mechanisms of Reelin activity in the postnatal brain. Our recent work further suggests an association between Reelin expression and traumatic brain injury in an animal model. We are currently investigating the potential novel role of Reelin in protecting the brain from the effects of injury and facilitating functional recovery.

2. Identification of cellular and molecular phenotypes of Tuberous Sclerosis Complex. Tuberous Sclerosis Complex (TSC) is a monogenetic developmental disorder characterized by tumor susceptibility in multiple organs, brain malformations, and neurological manifestations including epilepsy and autism. Despite considerable progress in understanding the genetics of the disease, effective treatments are still lacking, particularly with regard to the control of neurological symptoms. To better understand the mechanisms of disease we developed induced pluripotent stem cell (iPSC) lines from TSC patients that carry mutations in the TSC2 gene, as well as unaffected siblings, and derived neuronal progenitor cell (NPC) lines and differentiated neuronal cultures. In parallel, we generated a conditional knock out mouse line that lacks the Tsc2 gene specifically in excitatory neurons. We are currently investigating not only how the mutation affects the development of mutant neurons, but also how mutant neurons affect the development of surrounding brain cells, including inhibitory neurons and glia.

3. PI3K/Akt/mTOR signaling alterations in developmental brain disorders. Malformations of cortical development and brain overgrowth syndromes are developmental brain disorders often associated with epilepsy and cognitive dysfunction. These conditions frequently result from gene mutations in components of the PI3K/AKT/mTOR signaling pathway or the negative regulators PTEN, TSC1 and TSC2. The mutations can occur in the germline or in somatic neural progenitor cells at different stages of development, resulting in different degrees of brain malformation and neuronal hypertrophy. We utilize neuronal-specific Pten knock out mice to model activation of the PI3K signaling pathway, and pharmacological inhibitors to dissect the contribution of different components of the pathway to neuronal overgrowth and dysfunction. We recently demonstrated that specific inhibitors already approved for human use can restore normal size in cultured mutant neurons. Currently efforts are aimed at testing their effectiveness at restoring normal brain size and improving survival in vivo.

Publications


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