Olfactory neurons from bipolar patients

描述：（由申请人提供）本提案寻求一个结构化的研究培训计划，这将使Chang-Gyu Hahn。M.D.博士成为一名独立的研究者，因为他证明了嗅觉受体神经元（ORN）的效用，以检查双相情感障碍的神经生物学基础。 职业目标和目的：与能够应用最先进的分子技术，临床相关的研究范式，通过职业山羊 在ORN系统中，他提出了一个职业发展计划，重点是以下几个方面。1)离子成像和人ORN系统的神经生物学; 2）单细胞反义RNA扩增技术。 职业发展活动：候选人将接受人类嗅觉神经元离子成像（由Nancy罗森，PILD，共同导师指导）和单细胞分子技术（由James Eberwine，Ph.D.，共同导师）。博士 Karl Rickels将为特定目标2的治疗结局研究部分提供个人监督。Robert H.博士莱诺克斯将通过整合正式课程、实验室会议和监督来监督职业发展计划。 背景资料：ORN是唯一可以通过嗅上皮活检获得的CNS神经元，为研究活体神经元中的分子事件提供了独特的机会。通过在疾病的特定阶段获得ORN，结合对患者的纵向随访，神经元中分子事件的病理生理学意义可以与双相情感障碍联系起来。 假设：我们的初步数据表明双相情感障碍患者细胞内钙对异丙肾上腺素的反应发生了改变。I）作为双相情感障碍的特征，ORN对气味剂的细胞内钙反应主要是降低。2)双相患者的ORN中的伊卡反应降低是由于参与钙流的基因表达改变所致。3)响应于气味刺激的ORN的百分比在锂处理后总体上降低。4)来自双相患者的外植体培养物中的ORN将显示与患者体内ORN相似的伊卡反应。 具体目的：1）描述双相患者ORN中伊卡稳态和基因调控的特征和情绪状态依赖性改变。2)确定锂治疗后伊卡稳态的治疗相关变化。3)使用气味剂诱导的伊卡反应表征双相情感障碍患者的ORN培养物。

DESCRIPTION: (provided by applicant) This proposal seeks a structured research training program, which will enable Chang-Gyu Hahn. M.D. Ph.D. to become an independent investigator as he demonstrates the utility of olfactory receptor neurons (ORNs) to examine the neurobiology underlying bipolar disorder. Career Goals and Objectives: With the career goat of being able to apply the most advanced molecular techniques to clinically relevant research paradigms through the ORN system, he proposes a career development plan focusing on following areas. 1) ionic imaging and the neurobiology of the human ORN system and 2) Single cell antisense RNA amplification technique. Career Development Activities: The candidate will receive specialized training in ionic imaging in human olfactory neurons (guided by Nancy Rawson, PILD, co-mentor) and in single cell molecular technique (supervised by James Eberwine, Ph.D., co-mentor). Dr. Karl Rickels will provide individual supervision for the treatment outcome study component of the specific aim 2. Dr. Robert H. Lenox will oversee the career development program through integrating formal courses, lab meetings and supervisions. Background: ORNs, the only CNS neurons that are obtainable through olfactory epithelial biopsy, provide a unique opportunity to investigate molecular events in neurons from living subjects. By obtaining ORNs during specific stages of the illness, in conjunction with a longitudinal follow-up of patients, pathophysiologic significance of molecular events in neurons can be linked to bipolar disorder. Hypothesis: Our preliminary data suggest that intracellular calcium responses to odbrants are altered in bipolar disorder. I) Intracellular calcium responses of ORNs to odorants are predominantly a decrease as a trait of bipolar disorder. 2) The decreased ICa responses in ORNs from bipolar patients are due to altered expression of the genes that are involved in calcium flux. 3) The percentage of ORNs that respond to odorant stimulation is overall decreased following lithium treatment. 4) ORNs in explant cultures from bipolar patients will show similar ICa responses as in vivo ORNs of patients. Specific Aims: 1) To characterize trait- and mood state- dependent alterations in ICa homeostasis and gene regulation in ORNs from bipolar patients. 2) To identify therapeutically relevant changes in ICa homeostasis following lithium treatment. 3) To characterize ORN cultures from bipolar patients using odorant induced ICa responses.