Neuroprotective/Neurodevelopmental Effects-Antipsychotics in Adolescent Psychoses

描述（由申请人提供）：该提议寻求一段时间的有监督的科学培训，使Karin Borgmann-Winter医学博士能够发展成为一名独立的内科科学家。背景：早期干预对精神分裂症发展高风险的年轻人至关重要；然而，抗精神病药物对发育中的大脑的影响在很大程度上是未知的。临床前研究表明，不同的抗精神病药物可能影响大脑的神经营养或神经发育作用。然而，这些研究都是在动物大脑或体外细胞系中进行的，而从未在来自患者的神经细胞中进行过。研究项目：本研究将检查抗精神病药物对年轻精神病患者的潜在神经发育/神经营养作用。我们将利用嗅觉系统作为一个窗口，在其中检查与临床嗅觉测量和症状进展相关的神经元发育的分子和细胞生物学过程。我们将在抗精神病药物治疗前后从精神病患者的嗅觉活检组织中检查这些因素。我们将开发来自年轻精神病患者活检组织的嗅觉受体神经元的体外培养，并研究不同抗精神病药物及其神经递质结合谱和BDNF- TrkB信号之间的关系，作为抗精神病药物对神经发育影响的可能机制。环境：主要培训地点是细胞和分子神经病理学项目，神经生物学和行为中心的哈恩实验室以及宾夕法尼亚大学的精神分裂症研究中心。由Raquel E. Gur， M.D., PhD, Steven Arnold， M.D.和Chang-Gyu Hahn， M.D.博士领导的多学科指导将促进基础科学方法和年轻精神病患者临床观察的双向转化。研究职业发展：指导和正式课程将解决候选人的职业发展需要：1)获得设计和实施更复杂的细胞和分子生物学实验室方法所需的额外技能。2)接受心理物理嗅觉测试管理和嗅觉数据解释方面的培训。3)在评估和招募精神分裂症高风险青少年和处于精神病早期阶段的青少年方面发展额外的技能。4)发表研究成果并提交RO1。相关性：本提案将研究抗精神病药物对发育中的神经组织的潜在神经毒性或神经发育作用。这些信息对于确定早期干预对年轻人大脑发育的影响至关重要。

DESCRIPTION (provided by applicant): This proposal seeks a period of supervised scientific training to enable Karin Borgmann-Winter, M.D. to develop into an independent physician-scientist. Background: Early intervention is critically important for young individuals at high risk for the development of schizophrenia; yet the effects of antipsychotics on the developing brain are largely unknown. Pre-clinical studies suggested that different antipsychotics may impact on neurotrophic or neurodevelopmental effects in the brain. These studies, however, were conducted in animal brains or in vitro cell lines, but never in neural cells derived from patients. Research Project: This study will examine the potential neurodevelopmental/neurotrophic effects of antipsychotics in young subjects with psychoses. We will employ the olfactory system as a window in which to examine the molecular and cell biological processes of neuronal development in correlation with clinical olfactory measures and symptom progression. We will examine these factors in neurons from the olfactory biopsy tissues of psychotic individuals before and after antipsychotic treatment. We will develop in vitro cultures of olfactory receptor neurons derived from biopsy tissues from young individuals with psychoses and examine the relationships between different antipsychotics, their neurotransmitter binding profiles and BDNF- TrkB signaling as a possible mechanism for the effects of antipsychotics on neurodevelopment. Environment: The primary training sites are the Cellular and Molecular Neuropathology Program, the Hahn Laboratory of the Center for Neurobiology and Behavior and the Schizophrenia Research Center at the University of Pennsylvania. Multi-disciplinary mentoring led by and Raquel E. Gur, M.D., PhD, Steven Arnold, M.D. and Chang-Gyu Hahn, M.D. Ph.D. will facilitate bi-directional translation of methodological approaches in basic science and clinical observations in young individuals with psychoses. Research Career Development: Mentorship and formal coursework will address the candidate's career development needs to: 1) Acquire additional skills needed for the design and implementation of more complex cellular and molecular biological laboratory methods. 2) Obtain training in the administration of psychophysical olfactory tests and the interpretation of olfactory data. 3) Develop additional skills in the assessment and recruitment of adolescents at high risk for schizophrenia and in early stages of psychosis. 4) Publish research findings and submit an RO1. Relevance: This proposal will examine the potential neurotoxic or neurodevelopmental effects of antipsychotics on the developing neural tissues. Such information will be crucial for determining the effects of early intervention on the developing brains of young individuals. PUBLIC HEALTH RELEVANCE: This proposal will examine the potential neurotoxic or neurodevelopmental effects of antipsychotics on the developing neural tissues. Such information will be crucial for determining the effects of early intervention on the developing brains of young individuals.