Suicide is a major public health concern. About 30,000 people die each year by suicide in the USA alone, and about one million people die from it worldwide. Depression is a major risk factor for suicide. Several studies indicate that suicide s also associated with abnormal neurobiology, such as altered serotonin function and signaling mechanisms. Some studies also suggest abnormality of the immune function in depression and suicide. This is based on the observation of increased levels of proinflammatory cytokines, which are major mediators of immune function, in the serum and CSF of depressed and suicidal patients and the observation that administration of cytokines, such as TNF-?, to cancer patients induces symptoms similar to those of depression. Some recent studies indicate abnormalities of proinflammatory cytokines in the brain of depressed and suicide subjects. Cytokines and chemokine are important biological mediators of immune function. However, it appears that Toll-like receptors (TLR), which may be the first line of defense against pathogens and tissue damage, are also major mediators of innate immunity. Upon activation by specific ligands, TLRs induce downstream signals that lead to cytokine and chemokine production, which can initiate a localized inflammatory response. In order to examine the role of cytokines and TLRs in depression and suicide, we are proposing a comprehensive study of TLRs, cytokines and chemokines in postmortem brain of depressed and suicide subjects. The proposed studies are also based on our preliminary findings from a gene profile study indicating alteration (up- or down-regulation) of 14 genes in depressed suicide victims. These altered genes include certain cytokines, chemokines and TLRs. The main objectives of our proposed studies are to examine in detail the specific TLR and cytokine genes that are altered in suicide and depressed brain, and if these altered genes are specific to suicide (independent of diagnosis) or these alterations are also shared by non-suicide depressed subjects. To achieve this objective we will conduct a gene profile study in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of four groups of subjects which include: 1) normal controls, 2) depressed suicide, 3) non-depressed suicide, 4) non- suicide depressed subjects. We will then validate these findings by determining the mRNA and protein expression of altered genes, which we find to be about 14 in these subjects. These studies may be significant as they may result in identification of important bio- and vulnerability markers for depression and suicide and may provide useful targets, such as TLR-3, for developing newer therapeutic agents. This may be innovative as it may be the first comprehensive study of cytokines, chemokines and TLRs in depression and suicide and is significant for understanding the pathophysiology of depression and suicidal behavior and its treatment.

Public Health Relevance

Suicide is a major public health problem and about 30,000 people die of suicide in the USA every year, and about one million people die from it worldwide. However, the neurobiology of suicide is unclear. Abnormalities of cytokines, which are considered hormones of the immune system, have been implicated in suicide. Besides cytokines, chemokines and Toll-like receptors (TLRs) are other mediators of immune functions. In order to examine if abnormalities of immune function are involved in the pathophysiology of suicide we are proposing a study of neuroimmune genes in the postmortem brain of normal controls, suicides victims and depressed subjects. These studies may identify vulnerability genes for suicide and newer targets for developing therapeutic agents for treatment of depression and prevention of suicidal behavior. These studies may also provide an understanding of the role of the immune function in depression and suicide.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH098554-03
Application #
8680046
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Fuchsova, Beata; Alvarez Juliá, Anabel; Rizavi, Hooriyah S et al. (2016) Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression. Neuroscience 333:331-44
Pandey, Ghanshyam N; Rizavi, Hooriyah S; Zhang, Hui et al. (2016) The Expression of the Suicide-Associated Gene SKA2 Is Decreased in the Prefrontal Cortex of Suicide Victims but Not of Nonsuicidal Patients. Int J Neuropsychopharmacol 19:
Rizavi, Hooriyah S; Ren, Xinguo; Zhang, Hui et al. (2016) Abnormal gene expression of proinflammatory cytokines and their membrane-bound receptors in the lymphocytes of depressed patients. Psychiatry Res 240:314-20
Fuchsova, B; Alvarez Juliá, A; Rizavi, H S et al. (2015) Altered expression of neuroplasticity-related genes in the brain of depressed suicides. Neuroscience 299:1-17
Pandey, Ghanshyam N; Rizavi, Hooriyah S; Tripathi, Madhulika et al. (2015) Region-specific dysregulation of glycogen synthase kinase-3β and β-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia. Bipolar Disord 17:160-71
Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S et al. (2015) Proinflammatory cytokines and their membrane-bound receptors are altered in the lymphocytes of schizophrenia patients. Schizophr Res 164:193-8
Pandey, Ghanshyam N (2015) Cytokines as Suicide Risk Biomarkers. Biol Psychiatry 78:5-6
Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S et al. (2015) Abnormal gene expression of proinflammatory cytokines and their receptors in the lymphocytes of patients with bipolar disorder. Bipolar Disord 17:636-44
Pandey, Ghanshyam N; Rizavi, Hooriyah S; Ren, Xinguo et al. (2014) Toll-like receptors in the depressed and suicide brain. J Psychiatr Res 53:62-8
Pandey, Ghanshyam N (2013) Signal transduction abnormalities in suicide: focus on phosphoinositide signaling system. CNS Neurol Disord Drug Targets 12:941-53

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