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Laboratory of Genetic Neurobiology

Director: Russell L. Margolis, M.D.

Link to PubMed publications for Margolis RL

The Laboratory of Genetic Neurobiology currently focuses on five interrelated projects:

  1. Exploration of the genetic etiology and pathogenesis of psychiatric disorders, especially schizophrenia, using a candidate-gene approach.  We have detected families in which mutations in the genes DISC1 and NPAS3 segregate with schizophrenia (Sachs, 2005). Through the use of cell models, including iPS cells generated from family members (Chiang, 2011), animals models, and molecular and biochemical approaches, we propose to determine the relationship of the newly discovered mutations to normal gene function and pathways potentially involved in disease pathogenesis. These investigations are performed in collaboration with Dr. Christopher Ross and Dr. Frederick Nucifora. 
     
  2. The therapeutic implications of endogenous regulation of the Huntington’s disease (HD)gene expression. We have recently demonstrated that a transcript antisense to the HD gene serves to regulate expression of the HD gene (Chung, 2011). Current investigations involve exploring the interrelationship among the antisense transcript, the HD gene, and the HD expansion mutation. The goal is to determine if the antisense transcript can be upregulated, perhaps by small molecules, and thereby used as an endogenous knockdown strategy to decrease expression of the toxic HD mutation.
     
  3. Investigation of the pathogenesis of Huntington's disease like-2 (HDL2), another disorder clinically (Margolis et al, 2001) and genetically (Holmes, 2001) characterized in our laboratory. HDL2 is clinically indistinguishable from HD but is caused by a CTG expansion in an alternatively spliced exon of the gene junctophilin-3. Current research is focused on developing cell and animal models of HDL2 pathogenesis, and further defining the clinical, genetic, and epidemiological characteristics of the disease in humans (Rudnicki, 2007;  Rudnicki, 2008;  Seixas, 2012).  The guiding hypothesis is that comparison of HDL2 with HD will lead to the discovery of convergent modes of pathogensis central to both diseases. These investigations are performed in collaboration with Dr. Dobrila Rudnicki. 
     
  4. Therapeutics trials in Huntington’s diseae and schizophrenia.  In conjunction with the Huntington’s Disease Center (Dr. Christopher Ross, Director;  Dr. Frederick Nucifora), the laboratory is an active participant in HD clinical trials, including 2CARE (a five year clinical trial of co-enzyme Q10) and REACH2HD (a 6 month clinical trial of PBT-2), and KINECT-2 (a trial of a new agent for the treatment of antipsychotic-induced tardive dyskinesia). 
     
  5. Novel approaches to neuroimaging in schizophrenia.  In conjunction with Dr. Ross and Dr. Peter van Zijl and other faculty members of the Kirby Center, the lab is participating in the use of the Kirby Center ‘s powerful 7 Tesla scanner to examine anatomical, neurochemical, and functional abnormalities in schizophrenia.   We are particularly interested in the relationship of glutamate to cognition and visual stimuli, the multimodal application of various approaches to metabolic activity (BOLD, CMRO2, CBF, CBV, VASO) and the development for use in schizophrenia of methods such as chemical exchange saturation transfer (CEST) and quantitative susceptibility imaging (QSM).   

LAB MEMBERS

Russell L. Margolis, M.D.
Wang Zheng, M.D., Ph.D., post-doc
Chengxiu Zhang
Gregory Churchill, Research Coordinator (Huntington’s Disease Center)
Issel Lim, Ph.D., Post-doc (Kirby Center)

SELECTED PUBLICATIONS

Holmes SE, O'Hearn E, Callahan C, Hwang HS, Rosenblatt A, Ingersoll-Ashworth RG, Fleisher A, Stevanin G, Brice A, Potter NT, Ross CA, Margolis RL. A CTG trinucleotide repeat expansion in Junctophilin 3 is associated with Huntington's Disease-Like 2 (HDL2). Nature Genetics, 29 (2001): 377-378, 2001.

Chung DW, Rudnicki DD, Yu L, Margolis RL.  A natural antisense transcript at the Huntington’s disease repeat locus regulates HTT expression.  Human Molecular Genetics, 20 (2011):3467-77.

Chiang C-H, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL (co-corresponding author), Song H, Ming G-l.  Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation.  Molecular Psychiatry 16 (2011):358-60.

Seixas AI, Holmes SE, Takeshima H, Pavlovich A, Sachs N, Pruitt JL, Silveira I,  Ross CA, Margolis RL, Rudnicki DD.  Loss of junctophilin-3 contributes to Huntington’s Disease-like 2 pathogenesis, Annals of Neurology, 71(2012):245-257.

Yu L, Arbez N, Nucifora LG, Sells G, DeLisi L, Ross CA, Margolis RL, Nucifora FC. A mutation in NPAS3 segregates with mental Illness. Molecular Psychiatry, 2013, in press.

ACKNOWLEDGEMENTS

Work on all of these projects is performed in close collaboration with Drs. Christopher Ross, Fred Nucifora, Dobrila Rudnicki, and Misha Pletnikov within the Division of Neurobiology, and Drs. Juan Troncoso and Olga Pletnikova in the Department of Pathology, and Drs. Peter van Zijl,  Peter Baker, Richard Eden, Jun Hua, Craig Jones, Susumu Mori, and James Pekkar of the Kirby Center and Department of Radiology.

See also the Schizophrenia Center


    

 
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