Mechanisms and Significance of Stem Cell Fate Plasticity in the Adult Hippocampus

成体海马干细胞命运可塑性的机制及意义

基本信息

批准号：
8115042
负责人：
ALEX DRANOVSKY
金额：
$ 39.77万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-21 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115042
关键词：
Adult Affect Aging Alzheimer&apos s Disease Animal Housing Animals Anti-Anxiety Agents Antidepressive Agents Anxiety Area Autistic Disorder Behavioral Behavioral Genetics Birth Brain Brain Diseases Brain region Cell Lineage Cell Proliferation Cell Therapy Cells Chronic stress Cognitive Disease Emotional Environment Event Exposure to Family Foundations Fruit Gene Expression Genetic Glucocorticoid Receptor Glucocorticoids Goals Harvest Hippocampus (Brain)Human Knowledge Label Learning Life Experience Link Location Logic Maps Mental Depression Mental disorders Molecular Mus Neurons Patients Pharmaceutical Preparations Physiological Play Process Production Productivity Proliferating Proteins Reporting Research Personnel Resistance Rodent Role Schizophrenia Series Signal Transduction Social Environment Social isolation Stem cell transplant Stem cells Stress Structure System Testing Therapeutic Transgenic Animals Transplantation Work adult stem cell base brain tissue combat dentate gyrus environmental change environmental enrichment for laboratory animals experience genetic technology improved in vitro Assay in vivo insight nerve stem cell nervous system disorder neurogenesis novel public health relevance regenerative therapy research study response self-renewal stem stem cell fate stem cell fate specification stem cell niche stem cell population subventricular zone success

项目摘要

DESCRIPTION (provided by applicant): Mental illnesses like schizophrenia, autism and depression are common, destabilize families, and incur years of lost work productivity making them the most costly illnesses throughout the world. While some excellent treatment for depression and schizophrenia are available many patients are treatment resistant necessitating novel treatment approaches and no treatment widely accepted to be efficacious for Autism exists. For over thirty years treatment attempts to inject cultured nerve cells into brain areas that are affected by disease have produced disappointing results. The recent possibility of using stem cells for cell-based therapy is intriguing because while stem hold the potential to become neurons and other cells (multipotency). However, the cellular and molecular signals directing stem cells to become neurons remain elusive. One reason for limited success of transplantation therapy is that neurogenesis in the adult brain is restricted to two discrete regions. Other brain structures are thought to be non-permissive to the birth of new neurons. Amongst the two permissive structures is the hippocampus, which is affected by depression, anxiety, schizophrenia, autism and Alzheimer's disease. Several of these diseases were reported to be associated with disturbances in adult hippocampal neurogenesis. Experimental disruption of adult hippocampal neurogenesis leads to deficits in both learning and behavioral responses to antidepressant/antianxiety treatment in rodents. Therefore, hippocampal neurogenesis in the adult brain may be involved in disease states. The cellular and molecular events that permit neurogenesis in the adult brain remain unknown. Using a novel genetic technology we recently discovered that stem cells produce not only neurons, as currently accepted, but also more stem cells, depending on the experiences of the animal and on the location of the stem cell. We also developed a series of environmental manipulations that can drive stem cells to replicate themselves, to become neurons. The goal of the current proposal is to employ our genetic and behavioral systems to uncover the structural and molecular logic that makes neurogenesis and stem cell proliferation permissive in the adult brain. In a series of transplantation, gene expression analyses, and circuit-mapping experiments we intend to explore the mechanisms by which social environment can direct transplanted stem cells to proliferate and to become neurons. The experiments will help us determine how experience changes the stem cell environment and the stem cells themselves to regulate the production of new cells in the adult brain. I will also explore if this type of response to environmental changes helps the brain adapt to adversity by increasing the number of stem cells that can produce more neurons when life experiences become more favorable. Our results will lay the foundation for exploring how existing stem cells can be instructed to multiply and produce more neurons in the adult brain to improve brain function and possibly combat disease. This knowledge may also hold clues to overcoming resistance to neurogenesis in non-permissive brain structures. PUBLIC HEALTH RELEVANCE: The promise of cell-based therapy in the adult brain has not born fruit, but is actively pursued for brain disorders. Here the investigators propose to utilize their technical advances to identify changes in local brain microenvironments and in the stem cells, themselves, that instruct stem cells to proliferate or to make neurons and to examine if these changes can be co-opted for cell-based therapy in the brain. Finally, investigators will explore what role this "experience-directed" stem cell fate plasticity plays in adaptation to stress.

描述（由申请人提供）：精神分裂症、自闭症和抑郁症等精神疾病很常见，它们会破坏家庭的稳定，并导致多年的工作生产力损失，使其成为全世界代价最高的疾病。虽然抑郁症和精神分裂症有一些很好的治疗方法，但许多患者对治疗有抵抗力，需要新的治疗方法，并且不存在被广泛接受的对自闭症有效的治疗方法。三十多年来，尝试将培养的神经细胞注射到受疾病影响的大脑区域进行治疗，但结果却令人失望。最近使用干细胞进行基于细胞的治疗的可能性很有趣，因为干细胞具有成为神经元和其他细胞（多能性）的潜力。然而，指导干细胞变成神经元的细胞和分子信号仍然难以捉摸。移植治疗成功有限的原因之一是成人大脑中的神经发生仅限于两个离散的区域。其他大脑结构被认为不允许新神经元的诞生。海马体就是这两个许可结构中的一个，它受到抑郁症、焦虑症、精神分裂症、自闭症和阿尔茨海默病的影响。据报道，其中几种疾病与成人海马神经发生紊乱有关。成年海马神经发生的实验性破坏导致啮齿类动物对抗抑郁/抗焦虑治疗的学习和行为反应缺陷。因此，成人大脑中的海马神经发生可能与疾病状态有关。允许成人大脑神经发生的细胞和分子事件仍然未知。利用一种新颖的遗传技术，我们最近发现干细胞不仅能产生目前公认的神经元，还能产生更多的干细胞，具体取决于动物的经历和干细胞的位置。我们还开发了一系列环境操作，可以驱动干细胞自我复制，成为神经元。当前提案的目标是利用我们的遗传和行为系统来揭示成人大脑中允许神经发生和干细胞增殖的结构和分子逻辑。在一系列移植、基因表达分析和电路图谱实验中，我们打算探索社会环境引导移植干细胞增殖并成为神经元的机制。这些实验将帮助我们确定经验如何改变干细胞环境和干细胞本身来调节成人大脑中新细胞的产生。我还将探讨这种对环境变化的反应是否可以通过增加干细胞的数量来帮助大脑适应逆境，而当生活经历变得更加有利时，这些干细胞可以产生更多的神经元。我们的研究结果将为探索如何指示现有干细胞在成人大脑中繁殖并产生更多神经元以改善大脑功能并可能对抗疾病奠定基础。这些知识也可能为克服非许可性大脑结构中神经发生的阻力提供线索。公共健康相关性：成人大脑细胞疗法的前景尚未结出硕果，但正在积极寻求针对大脑疾病的治疗。在这里，研究人员建议利用他们的技术进步来识别局部大脑微环境和干细胞本身的变化，这些变化指导干细胞增殖或产生神经元，并检查这些变化是否可以用于基于细胞的治疗在大脑中。最后，研究人员将探讨这种“经验导向”的干细胞命运可塑性在适应压力中发挥什么作用。