Bipolar Disorder (BD) is a chronic debilitating illness with substantial societal burden. A major impediment in our ability to develop improved therapeutics for BD is the fact that our understanding of its pathophysiology is incomplete. Lithium, used for treatment of BD, alters steady-state mRNA levels of a large number of genes;notably GSK-32, inositol monophosphatase (IMPase), MIP Synthase, Bcl-2, Akt, Protein Kinase C, MARCKS, insulin-like growth factor binding protein-2 (IGFBP-2), and ERK. But it remains unknown, how any of these molecular changes bring about clinical response, if, at all. Hitherto, studying cellular and molecular effects of lithium in the central nervous (CNS) tissues of living BD patients has been infeasible. Although postmortem brains have been useful for studies of biomarkers, they are insufficient to capture state-dependent molecular signature of BD. Blood cells may not reflect adequately, molecular disposition in neuronal cells. In this study, we propose use of olfactory epithelium (OE) via nasal biopsy, combined with novel laser-captured microdissection to elucidate molecular and cellular markers of prospectively-determined clinical response to lithium. This will be followed by determination of parallel dispositions of these molecular patterns in lymphoblasts obtained from same subjects, for possible clinical and prognostic utility of blood markers. OE is a unique part of the CNS that continually regenerates and differentiates into mature olfactory receptor neurons (ORNs) throughout life. This presents an avenue to examine the neurodevelopmental hypotheses of BD through examination of changes in the densities of proliferating (p75NGRF+) neuronal precursors and mature (olfactory marker protein+) neurons (surrogate markers of neurogenesis and neuronal survival in OE). Also of particular interest, dysregulation of genes relevant to lithium action, and therefore BD may be reflected in deficits in olfactory functions. Therefore, combined study of molecular mechanisms underlying mood stabilization in olfactory tissue and tests of olfactory function could advance our understanding of the pathophysiology of BD and generate new data resource to study other pathoetiologies of BD. Furthermore, parallel studies of validated genes (from OE studies) in lymphoblasts (LB), confirmed by confirmed protein studies, may preempt future clinical and prognostic utility of blood markers.
In specific aim 1 of this project, we propose to use our successful recruitment approach of BD subjects, to ascertain 40 non-medicated, non-smoking subjects with acute episodes of BD and 20 gender-, age-, and race- matched non-smoking normal controls (CTL) for this study.
In specific aim 2, we will: a) compare BD and CTL on mRNA levels of (above-stated) 9 candidate genes of lithium action measured via RT-PCR, and b) examine the effect of lithium-associated changes in mRNA levels on clinical response (LR) in the BD subjects. To further illuminate cellular mechanisms of mood stabilization in specific aim 3, we will employ immunohistochemical techniques to examine densities of cell type-specific antibodies directed at the proliferating low-affinity nerve growth factor receptor (p75NGFR), postmitotic immature neurons (growth- associated protein 43 [GAP43]), and olfactory marker protein (OMP) in OE samples of all participants pre- and post-treatment, to determine if increased density of proliferating neuronal precursors and mature neurons (surrogate markers of neurogenesis and neuronal survival, respectively) are mediators of the effect of lithium- associated molecular alterations on LR. In other studies, we will: 1) examine differences in olfaction between BD and CTLs;2) determine the association between baseline gene activity and olfactory function, and the impact of gender on these associations;3) determine the utility of baseline olfactory function and lithium- associated changes in olfaction as surrogate markers of BD severity and mood stabilization;and 4) determine parallel dispositions between OE and LB on molecular markers of lithium action. Accomplishment of these aims will advance our understanding of the pathophysiology of BD, facilitate development of novel and improved therapeutics with specific desired effect on mood stabilization, and generate new data resource for team of scientists to further investigate other pathoetiologies of BD.
We are well overdue for better understanding of the pathophysiology of, and for development of improved therapeutics of Bipolar disorder (BD), a condition that causes extensive illness burden to sufferers and substantial economic burden to the society. We have now developed novel techniques to prospectively study cellular and molecular determinants of mood stabilization during lithium treatment, using a central nervous system tissue, olfactory epithelium (OE) of acutely ill BD patients. The goals of this proposal are: 1) recruit autely ill BD patients to assess clinical symptoms and obtain repeated OE biopsies, before and after lithium monotherapy;2) identify molecular markers whose alterations predict clinical response;3) determine if the effect of lithium-induced molecular alterations is mediated through enhanced neurogenesis and neuronal survival;and 4) examine olfactory function and gene activity in blood cells for utility as markers of disease-associated, lithium-modifiable molecular dysregulation of BD. This study could enhance development of targeted therapeutics for BD.
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