Neurosurgery
P.O., Box 208082
New Haven, CT 06520-8082
Tel: 203.785.2805
Fax: 203.785.6916
neurosurgery@yale.edu
Our research is generally concerned with the study of molecular mechanisms governing the development of the vertebrate brain. We are particularly interested in addressing how the perturbation of basic biological mechanisms leads to clinically significant brain pathologies. Working closely with other research groups in the Yale Program on Neurogenetics, we study the molecular and cellular mechanisms underlying neurodevelopmental disorders associated with specific genetic lesions. Insight into these questions will shed light on fundamental neurodevelopmental processes and provide information relevant for the design of therapeutic approaches.
Blood-tissue barriers represent the major interfaces between the central nervous system and peripheral circulation. Barriers are found in the endothelium of the brain vasculature (the blood-brain barrier) and the epithelium of the choroid plexus (the blood-CSF barrier). They have an important neuroprotective function but also limit drug delivery into the brain. We are studying the cellular and molecular mechanisms responsible for the establishment of brain barriers during embryogenesis using the mouse as our main experimental system. Our specific goal is to gain insight into the neuroprotective blood-CSF barrier by a developmental, genetic and molecular analysis of the choroid plexus while exploring its known relationship to the development of hydrocephalus, a common neurodevelopmental problem that requires surgical intervention.
Genetic analyses have recently linked mutations in specific genes to developmental neuropsychiatric disorders including Tourette syndrome, Mental Retardation and Autism Spectrum Disorders. Our collaborative work focuses on these disorders trying to understand the underlying molecular mechanisms, using the genetic evidence as our starting point. All three disorders have heterogeneous etiology, however strong evidence suggests a significant genetic contribution.
Efforts in the State lab have pointed to the gene SLITRK1 (SLIT and TRK-like family 1) as a candidate for involvement in rare cases of Tourette syndrome (Abelson et al., 2005) and have also implicated the neuronal cell adhesion molecules CNTN4 (Contactin 4) and CNTNAP2 (Contactin-associated protein 2) respectively in Mental Retardation (Fernandez et al., 2004) and Autism Spectrum Disorders (Bakkaloglu et al., 2008). We are using molecular and cell biological approaches to characterize the functions of Slitrk1, Cntn4 and Cntnap2 in brain development and to explore the impact that disease-linked variants in these genes have on brain morphogenesis.
Efforts in the Gunel lab have implicated three genes in the pathogenesis of familial cerebral cavernous malformations, monogenic forms of hemorrhagic stroke characterized by vascular abnormalities that are almost exclusively seen in the central nervous system (Gunel et al., 2002; Guzeloglu-Kayisli et al., 2004; Seker et al., 2006; Tanriover et al., 2008). We are currently exploring the functions of one of these genes, Ccm3, in brain development using molecular approaches as well as mouse models.
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common hereditary monogenic form of ischemic stroke underlied by vascular abnormalities (for a recent review, see Louvi et al., 2006). CADASIL has been associated with highly stereotypical mutations in the extracellular domain of the Notch 3 receptor, exclusively affecting cysteine residues. We are using animal and cell-based models to gain insight into the molecular underpinning of CADASIL-linked mutations and to characterize the physiological, cellular and molecular properties of cells and tissues affected by abnormal Notch 3 activity (Arboleda-Velasquez et al., 2008).
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Yale School of Medicine
Last updated
7/16/08
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