Molecular mechanisms underlying mood stabilization in bipolar disorder

Evaristus A. Nwulia, M.D., MHS

Howard University

Funded in December, 2010: $250000 for 2 years
LAY SUMMARY . BIOGRAPHY .

LAY SUMMARY

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Through this pilot study, investigators will determine the feasibility of identifying molecular targets of the mood-stabilizing drug lithium in acutely ill patients with bi-polar disorder which may serve as biomarkers for testing potential new drugs.

Lithium is the current standard of treatment for patients with bi-polar disease. While the drug is known to induce multiple biochemical and molecular effects—including actions on cells’ signaling, hormonal regulation and gene expression—scientists do not yet know exactly how lithium exerts its therapeutic effects. Understanding this may lead to development of more effective treatments with less serious side effects. The investigators will undertake a pilot study in patients with acute bi-polar disease and healthy volunteer participants (controls) to determine if it is feasible to identify lithium’s molecular targets for stabilizing mood.  Prior animal research has identified nine potential molecular targets that may be sensitive to lithium’s actions. These nine molecules are thought to be present in the brain’s limbic regions that are believed to play a central role in regulating emotions. Additionally, growing evidence, from animal studies suggests that these same molecules also may be present in the tissue that lines the nose (olfactory epithelium), based on the understanding that these two structures undergo development at the same time in the embryo.  While it is not feasible to correlate actions of molecules with behavioral changes in the animal model, it would be possible to do so in patients.    

In collaboration with researchers at Johns Hopkins University over the next two years, therefore, the Howard University investigators will study olfactory epithelium tissue biopsies in 16 patients with bi-polar disease undergoing lithium treatment for six weeks. They first will determine whether some or all of the nine candidate molecular lithium targets are found in patients’ olfactory epithelium tissue.  Next, they  will determine whether changes occur in those molecules after patients undergo six weeks of lithium therapy.  They then will assess whether the changes are associated with remission of patients’ mania and/or depression. If investigators find that molecules have changed only in patients and not in the eight control participants, the evidence would suggest that lithium is acting on those molecules.  If so, these molecules may serve as biomarkers of the disease..Additionally, the researchers will undertake genetic studies to develop initial data on genes that may be involved in producing these molecules, to begin to try to develop predictors of the risk of developing bi-polar disease. The findings are anticipated to lead to large-scale studies funded by others to confirm the biomarkers and to further explore genetic predictors of disease risk. 

Significance:  Identification of biomarkers could lead to improved treatment for bi-polar disease, by enabling scientists to discover new experimental therapies that target these molecules more effectively and with fewer side-effects than lithium.

INVESTIGATOR BIOGRAPHIES

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Evaristus A. Nwulia, M.D., MHS

BIOGRAPHICAL SKETCH

Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person.  DO NOT EXCEED FOUR PAGES.

 

NAME

Evaristus A. Nwulia, M.D. MHS

POSITION TITLE

Assistant Professor

eRA COMMONS USER NAME

enwulia1

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

YEAR(s)

FIELD OF STUDY

University of Benin, Nigeria

MBBS

1987-1994

Medicine

Johns Hopkins School of Medicine, Baltimore

Residency

1999-2003

Psychiatry

Johns Hopkins University School of Medicine

Post-doctoral fellowship

2003-2005

Psychiatric Genetics

Johns Hopkins University School of Public    Health

MHS

2006-2008

Human Genetics/Genetic

  Epidemiology

 

 

A. Personal  Statement

Dr. Nwulia is a clinical neuroscientist who combines clinical training in affective disorders and post-doctoral trainings in basic genetics, epidemiology, biostatistics and biocomputing into a new career path in translational neuroscience. Currently, he provides bioinformatics support for the Molecular Psychiatry Laboratory of Dr. Akira Sawa at Johns Hopkins University, and also a co-Investigator in a study investigating the roles of MHC Class I molecules and nicotine NMDAR neurotransmitter in schizophrenia. He currently has institutional supports to study molecular signature of lithium response (i.e. mood stabilization). Dr. Nwulia’s long-term goals are to characterize immune and other molecular cascades in the mechanism of major psychiatric disturbances.

B. Positions and Honors

Positions and Employment

  • Research Coordinator, Maryland Treatment Center, Baltimore

1999-2003       Resident Physician, Department of Psychiatry, John Hopkins Hospital, Baltimore

  • Fellow, Department of Psychiatry, Psychiatric Genetics Division, John Hopkins Hospital

2003-2005      Attending Psychiatrist, Mountain Manor Treatment Center, Baltimore, Maryland

2005-Present   Assistant Professor, Department of Psychiatry, Howard University, Washington, DC

2009-Present   Member, Institutional Review Board (IRB), Howard University

2009-Present   Principal Investigator of Neurophysiology Core, Howard University.

Honors and Awards

June 2003              NIH Neuroscience Training Award, Johns Hopkins University

August 2009         Alcohol Travel Award for the 2009 World Congress in Psychiatric Genetics (WCPG).

September 2009    Early Career Investigator Track at the XVII World Congress of Psychiatric Genetics.

December 2009     Diversity Bank Invitation, American College of Neuropsychopharmacology (ACNP)

 

C. Selected Peer-Reviewed Publications

  • Nwulia A, et al.  Knowledge, attitude and practice towards AIDS among civil servants in Nigeria.  J R Soc Health. 1995 Feb;115(1):19-22
  • Nwulia EA.  Drug abuse in Youths (Book). ISBN 978338340-X. Bayomedia, Nigeria. May 1996.
  • Nwulia EA, et al.  Bipolar Approach Model of Drug Abuse Prevention.  UNDCP Manual, August 1996.
  • Nwulia EA, et al.  Thrombocytopenia of Alcoholism:  an interesting correlation with biological markers.  American College of Physicians. May 2000.
  • Maeda K, Nwulia EA, Chang J, McInnis M, Sawa A.  Differential Expression of Disrupted-in-Schizophrenia (DISC 1) in Bipolar Disorder. Biological Psychiatry. 2006 Nov 1;60(9):929-35
  • Payne JL, Roy PS, Nwulia EA.  Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder. J Affect Disorder. 2007 Apr;99(1-3):221-9
  • Nwulia EA, Zandi PP, Mackinnon DF, DePaulo JR Jr, McInnis MG. Genome-Wide Scan of Bipolar II Disorder. Bipolar Disorder. 2007 Sep;9(6):580-8.
  1. Nwulia EA, Zandi PP, McInnis MG, DePaulo JR Jr, MacKinnon DF: Rapid switching of mood in families with familial bipolar disorder. Bipolar Disord. 2008 Jul;10(5):597-606.
  2. Zhang D, Cheng L, Qian Y, Nurnberger J, Edenberg HJForoud T, Sheftner W, Lawson WB, Nwulia EA, Berrettini W, Potash JB, Gershon ES et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry. 2008 Dec 30.
  3. Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W, Byerley W, Coryell W, Craig D, Edenberg HJ, Eskin E, Foroud T, Gershon E, Nurnberger J, Nwulia EA, Paschall J, Potash JB, Rice J, Schulze TG, Scheftner W, Panganiban NJ, Kelsoe JR. Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry. 2009 Jun 2
  4. Hsu P, Nwulia EA, Sawa A. Using Bioinformatic Tools. Am J Psychiatry 166:854, August 2009
  5. Nwulia EA, Hipolito M, Lawson WB, Nurnberger JI Jr, NIMH Genetic Collaborative Group: Genetics of Alcohol Dependence Comorbidity in Bipolar Disorder I (Under Review)
  6. Nwulia EA, Hipolito M, Lawson WB, Nurnberger JI Jr, NIMH Genetic Collaborative Group: Genetics of Alcohol Dependence Comorbidity in Bipolar Disorder II (Under Review)

 

  • Research Support

Completed and Ongoing:

9/22/2005 – 6/30/2010:  “Genetics of Early Onset Depression.” NIMH 1R01 MH075131-04.  The major aim is to identify the genetic basis of depression in African-Americans. Co-Investigator.

4/1/2008 – 4/30/2011: Genomewide Association Study of Bipolar Disorder and Subphenotypes. Sponsor:

Genetic Association Information Network (GAIN) and NHGRI. Principal Investigator.

7/1/2009 – 6/30/2011: “Relationship of immune molecules (MHC Class 1, Complement) and

key neurotransmitter (nicotine, NMDAR) in postmortem brain of patients with schizophrenia. SMRI (Stanley Medical Research Institute) #09R-2137. Co-Investigator.

     PENDING AWARD

Developing Capacity for Biomedical Signal Processing and Integration of Cognitive and Behavioral Function Data in a Candidate Gene Study of Neurobehavioral Response to Alcohol Challenge at Howard University. Funding Source: R03, NIAAA; NIH Award Council Meeting, 08/2010.

INSTITUTIONAL SUPPORT

7/1/2010 – 6/31/2010: Molecular Mechanism of Lithium Action in Bipolar Disorder Using Olfactory Epithelium. Funding Source: Supported by Molecular Psychiatry Division of Johns Hopkins University and Department of Psychiatry, Howard University (IRB-10-MED-40). Principal Investigator.