A5004243222- Hereditary Neurological Disorders
- Connexins and lens biology
- Botulinum Toxin and Related Neurological Disorders
- RNA regulation and disease
- Genetic Neurodegenerative Diseases
- Nerve injury and regeneration
- Angiogenesis and VEGF in Cancer
- Calpain Protease Function and Regulation
- Yersinia bacterium, plague, ectoparasites research
- Neurological diseases and metabolism
- Heat shock proteins research
- Protease and Inhibitor Mechanisms
- Virus-based gene therapy research
- Barrier Structure and Function Studies
- Peripheral Neuropathies and Disorders
- Mitochondrial Function and Pathology
- Neurogenetic and Muscular Disorders Research
- Cancer Treatment and Pharmacology
- Neuroinflammation and Neurodegeneration Mechanisms
- Multiple Sclerosis Research Studies
- Neurogenesis and neuroplasticity mechanisms
- ATP Synthase and ATPases Research
- Biochemical effects in animals
- RNA Research and Splicing
- Metabolism and Genetic Disorders
Cyprus Institute of Neurology and Genetics
2015-2025
Temple University
2011
University of Pennsylvania
2010
Drexel University
2004
Hahnemann University Hospital
2001
The gap junction (GJ) protein connexin32 (Cx32) is expressed by myelinating Schwann cells and oligodendrocytes mutated in X-linked Charcot-Marie-Tooth disease. In addition to a demyelinating peripheral neuropathy, some Cx32 mutants are associated with transient or chronic CNS phenotypes. To investigate the molecular basis of these phenotypes, we generated transgenic mice expressing T55I R75W mutation an IRES-EGFP, driven mouse Cnp promoter. transgene was throughout cells. Both were localized...
Gap junctions (GJs) are vital for oligodendrocyte survival and myelination. In order to examine how different stages of inflammatory demyelination affect GJs, we studied the expression oligodendrocytic connexin32 (Cx32) Cx47 astrocytic Cx43 in experimental autoimmune encephalomyelitis (EAE) mouse model multiple sclerosis (MS) induced by recombinant myelin glycoprotein. EAE was characterized remissions relapses with axonal loss. Formation GJ plaques quantified relation lesions normal...
Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in SH3TC2 gene. Sh3tc2−/− mice represent a well characterized model developing early onset progressive peripheral with hypo- and demyelination, slowing nerve conduction velocities disturbed nodal architecture. The aim this project was to develop gene replacement therapy for treating rescue phenotype mouse model. We generated lentiviral vector...
Abstract Mutations in the GJB1 gene, encoding gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using AAV9 vector to deliver GJB1/Cx32 under myelin zero ( Mpz ) promoter targeted expression Schwann cells. Lumbar intrathecal injection of -Mpz.GJB1 resulted widespread biodistribution peripheral nervous system including lumbar roots, sciatic and femoral nerves, as...
The X-linked demyelinating/type I Charcot-Marie-Tooth neuropathy (CMT1X) is an inherited peripheral caused by mutations in GJB1, the gene that encodes gap junction protein connexin32. Connexin32 expressed myelinating Schwann cells and forms junctions noncompact myelin areas, but axonal involvement more prominent compared with other of demyelinating disease. To clarify cellular molecular mechanisms pathology CMT1X, we studied Gjb1-null mice at early stages (i.e. 2-4 months old) neuropathy,...
Gap junctions are essential for glial cell function and have been increasingly implicated in multiple sclerosis (MS). Because increasing cortical abnormalities correlate with disease progression cognitive dysfunction, we examined the expression of oligodendrocytic connexin32 (Cx32) Cx47 their astrocytic partners Cx30 Cx43 lesions normal-appearing gray matter (NAGM) MS patients. Postmortem brain tissue samples from 9 cases were compared 10 controls using real-time polymerase chain reaction,...
X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited demyelinating neuropathy caused by loss-of-function mutations in the GJB1 gene, encoding gap junction protein connexin32 (Cx32). Cx32 plays a critical role Schwann cell function and myelin formation peripheral nervous system. We have developed gene replacement therapeutic approach using humanized AAVrh10 vector construct expressing under control of cell-specific human zero (MPZ) promoter. Lumbar intrathecal injection increasing...
Pelizaeus-Merzbacher-like disease or hypomyelinating leukodystrophy-2 is an autosomal recessively inherited leukodystrophy with childhood onset resulting from mutations in the gene encoding gap junction protein connexin 47 (Cx47, encoded by GJC2). Cx47 expressed specifically oligodendrocytes and crucial for junctional communication throughout central nervous system. Previous studies confirmed that a cell autonomous loss-of-function mechanism underlies transgenic oligodendrocyte-specific...
Gap junction beta-1 (GJB1) gene mutations affecting the gap protein connexin32 (Cx32) cause X-linked Charcot-Marie-Tooth disease (CMT1X), a common inherited neuropathy. Targeted expression of virally delivered Cx32 in Schwann cells following intrathecal injection lentiviral vectors knockout (KO) mouse model has led to morphological and functional improvement. To examine whether this approach could be effective CMT1X patients expressing different mutants, we treated transgenic KO mice T55I,...
X-linked Charcot-Marie-Tooth disease (CMT1X) is a common inherited neuropathy caused by mutations in the GJB1 gene encoding gap junction protein connexin32 (Cx32). Clinical studies and models indicate that mainly results from Schwann cell autonomous, loss-of-function mechanisms; therefore, CMT1X may be treatable replacement.A lentiviral vector LV.Mpz-GJB1 carrying under cell-specific myelin zero (Mpz) promoter was generated delivered into mouse sciatic nerve single injection immediately...
X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss function gap junction protein connexin32 (Cx32). The aim this study was to examine whether delayed replacement therapy after onset peripheral neuropathy can provide a therapeutic benefit in Gjb1-null/Cx32 knockout model CMT1X. After delivery LV-Mpz.GJB1 lentiviral vector by single lumbar intrathecal injection into 6-month-old Gjb1-null...
X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions systemic inflammation and metabolic stress. To clarify underlying mechanisms phenotypes in we studied mouse model induced lipopolysaccharide (LPS) injection to compare wild type (WT), (Cx32)...
Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. highly expressed in myelinating Schwann cells. CMT4C a childhood-onset progressive disease without effective treatment. Here, we generated therapy for mediated an adeno-associated viral 9 vector (AAV9) to deliver the human Sh3tc2
Abstract Gap junctions (GJs) coupling oligodendrocytes to astrocytes and other are formed mainly by connexin47 (Cx47) a smaller portion connexin32 (Cx32). Mutations in both connexins cause inherited demyelinating disorders, but their expression is also disrupted multiple sclerosis (MS). To clarify whether the loss of either Cx47 or Cx32 could modify outcome inflammation myelin loss, we induced experimental autoimmune encephalomyelitis (EAE) fully backcrossed knockout (KO) Cx47KO mice...
Glial gap junction proteins, called connexins (Cxs), form junctions in the central nervous system to allow bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement inheritable diseases and use experimental animal models that closely mimic such revealed critical role glial GJs myelination homeostasis. Cxs are also implicated acquired demyelinating disorders, as Multiple Sclerosis (MS) Alzheimer's disease (AD). Animal human studies have a astrocytic Cx43...