The goal of this hypothesis-generating research proposal is to investigate the molecular mechanisms involved in the central nervous system (CNS) response to systemic inflammation. The central response to systemic inflammation will be monitored by DNA microarray technology, which allows the simultaneous monitoring of the expression of thousands of genes. Our proposed studies will systematically assess several parameters that will provide guidance for the use of microarrays in the study of dissected discrete regions of whole CNS tissue and will include extensive validation of the findings by real-time PCR. We will assess parameters such as coefficients of intraassay (interslide) and interassay variation, and the inclusion of brain region specific and inflammation cDNA controls. We will evaluate data obtained using: (1) three methods of tissue dissection, (2) two brain regions (hypothalamus and hippocampus), and (3) a specific transgenic model that shows meaningful biological outcome with our chosen paradigm. The validation of these parameters and the implications of our data analyses will be useful in the evaluation of microarray as a technique for comprehensive surveys of CNS transcriptional changes that will be likely to occur upon the completion of current genomic projects. To study CNS gene transcription we will use a rodent model of systemic inflammation response syndrome (SIRS or Sepsis) caused by peripheral (intraperitoneal) lipopolysaccharide (LPS) administration. This is a clinically relevant model of inflammation that induces acute transcription of multiple genes in the CNS. The areas to be studied, hypothalamus and hippocampus, are the sites for the regulation of clinically relevant neuroendocrine responses to inflammation. In addition, the proposed studies will result in new and valuable data related to transcription regulation that are important in defining signaling pathway mechanisms in the CNS during states of inflammation. The proposed studies will result in new data that will be needed for us to generate novel testable hypotheses, which will provide the framework for future R0l applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH062777-02
Application #
6539208
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Brady, Linda S
Project Start
2001-07-30
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$152,500
Indirect Cost
Name
University of California Los Angeles
Department
Psychiatry
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wong, Ma-Li; Dong, Chuanhui; Flores, Deborah L et al. (2014) Clinical outcomes and genome-wide association for a brain methylation site in an antidepressant pharmacogenetics study in Mexican Americans. Am J Psychiatry 171:1297-309
Licinio, J; Negrao, A B; Wong, M-L (2014) Plasma leptin concentrations are highly correlated to emotional states throughout the day. Transl Psychiatry 4:e475
Wong, M-L; Dong, C; Andreev, V et al. (2012) Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Mol Psychiatry 17:624-33
Paz-Filho, Gilberto; Licinio, Julio; Wong, Ma-Li (2010) Pathophysiological basis of cardiovascular disease and depression: a chicken-and-egg dilemma. Rev Bras Psiquiatr 32:181-91
Licinio, Julio; Dong, Chuanhui; Wong, Ma-Li (2009) Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry 66:488-97
Dong, C; Wong, M-L; Licinio, J (2009) Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry 14:1105-18
Andreev, V P; Paz-Filho, G; Wong, M-L et al. (2009) Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 41:142-51
Paz-Filho, G J; Ayala, A; Esposito, K et al. (2008) Effects of leptin on lipid metabolism. Horm Metab Res 40:572-4
Wong, M-L; Dong, C; Maestre-Mesa, J et al. (2008) Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13:800-12
Wong, Ma-Li; Dong, Chuanhui; Esposito, Karin et al. (2008) Elevated stress-hemoconcentration in major depression is normalized by antidepressant treatment: secondary analysis from a randomized, double-blind clinical trial and relevance to cardiovascular disease risk. PLoS One 3:e2350

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