Lithium responsiveness

描述（由申请人提供）：多达三分之一的双相情感障碍（BD）患者在临床上对情绪稳定剂治疗无反应，因此遭受毁灭性的临床过程。几十年来，在寻找情绪稳定剂的分子靶点的研究中，已经证明情绪稳定剂，特别是锂，强烈地调节各种细胞内信号传导机制。然而，这些药物是否调节人类神经元中的细胞内信号传导机制，或者这种调节是否实际上有助于治疗功效，仍然是未知的。我们建议通过测试锂对双相情感障碍（BD）患者嗅神经上皮（OE）活检获得的神经组织的影响来解决这些问题。生物过程的几个维度可以介导细胞内信号传导和复杂的行为表现，例如治疗功效：信号传导->基因调节->细胞输出->神经元功能->情绪状态。为了测试这些生物学过程的治疗相关性，我们将评估BD患者的OE活检组织，并将细胞内信号传导机制、基因调控和神经元功能与其对锂治疗的临床反应性联系起来。为此，我们将在一对临床研究中招募BD患者;一个是横断面研究，一个是前瞻性研究。横断面研究（Aim 1a，第I组患者）将测试OE组织中的分子和细胞参数，作为影响患者一生中对锂的反应的分子谱。前瞻性研究（Aim 1b，第II组患者）将测试信号调节与急性情绪发作改善之间的关系。为了实现目标1的目的，我们将在活检后立即检查患者的OE组织（离体范例），以在手术时捕获神经元信号。为了追踪这些信号变化到它们的细胞输出或神经元调制，我们将研究基因转录和上游分子事件。使用体外OE研究范式，我们将进行详细的分析上游分子事件和下游转录调控（目标2）。为了进一步将这些分子事件与治疗效果背景下的细胞功能联系起来，我们将研究I组和II组患者OE组织中的神经营养/保护作用。此外，我们将测试BDNF或NMDA受体传递作为OE培养物中神经营养/保护作用的分子机制（目的3）。该项目将首次尝试使用患者的神经元细胞连接信号->神经元功能->治疗反应级联中的点，因此，将解决分子和细胞途径以及关于BD治疗抗性的神经生物学基础的特定机制假设。

DESCRIPTION (provided by applicant): As many as a third of persons with bipolar disorder (BD) are clinically unresponsive to treatment with mood stabilizers and thus suffer a devastating clinical course. Studies over decades, in search of molecular targets of mood stabilizers, have demonstrated that mood stabilizers, lithium in particular, robustly regulate various intracellular signaling mechanisms. It is still unknown, however, whether these drugs regulate intracellular signaling mechanisms in human neurons or if such regulation actually contributes to therapeutic efficacy. We propose to address these issues by testing the effects of lithium on neural tissues obtained from biopsies of the olfactory neuroepithelium (OE) of bipolar disorder (BD) patients. Several dimensions of biological processes may mediate intracellular signaling and complex behavioral manifestations such as therapeutic efficacy: signaling -> gene regulation -> cellular outputs -> neuronal functions -> mood states. To test therapeutic relevance of these biological processes, we will assess BD patients' OE biopsy tissues and relate intracellular signaling mechanisms, gene regulation and neuronal function to their clinical responsiveness to lithium treatment. To that end, we will recruit BD patients in a pair of clinical studies; one cross-sectional and one prospective. The cross sectional study (Aim 1a, Group I patients) will test molecular and cellular parameters in OE tissues as a molecular profile that influences the patient's response to lithium across their lifetime. The prospective study (Aim 1b, Group II patients) will test the relationships between signaling modulation and improvement of acute mood episodes. To accomplish the objectives of Aim 1, we will examine OE tissues of patients immediately after biopsy (ex vivo paradigm) to capture neuronal signaling at the time of procedure. To trace these signaling changes to their cellular outputs or neuronal modulation, we will examine gene transcription and upstream molecular events. Using an in vitro OE study paradigm, we will conduct a detailed analysis of upstream molecular events and downstream transcriptional regulation (Aim 2). To further connect these molecular events to cellular functions in the context of therapeutic efficacy, we will examine neurotrophic/protective effects in the OE tissues of Group I and Group II patients. In addition, we will test BDNF or NMDA receptor transmission as molecular mechanisms underlying neurotrophic/protective effects using in OE cultures (Aim 3). This project will, for the first time, attempt to connect the dots in the cascade of signaling -> neuronal functions -> treatment response using patients' neuronal cells and, as such, will address molecular and cellular pathways and specific mechanistic hypotheses regarding the neurobiological basis of treatment resistance in BD.