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：
8246525
负责人：
ALEX DRANOVSKY
金额：
$ 39.68万
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/8246525
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）：精神病，自闭症和抑郁症等精神疾病是普遍的，破坏家庭的稳定，并蒙受了多年的工作生产力，使它们成为全世界最昂贵的疾病。尽管有一些出色的抑郁症和精神分裂症治疗，许多患者具有耐药性，需要采用新颖的治疗方法，并且没有被广泛接受以对自闭症有效的治疗。三十多年来，治疗试图将培养的神经细胞注入受疾病影响的大脑区域，导致了令人失望的结果。使用干细胞进行基于细胞的治疗的最新可能性是有趣的，因为尽管Stem具有成为神经元和其他细胞的潜力（多能力）。然而，引导干细胞成为神经元的细胞和分子信号仍然难以捉摸。移植疗法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区域。其他大脑结构被认为对新神经元的诞生是不可能的。在两个允许结构中，海马受到抑郁，焦虑，精神分裂症，自闭症和阿尔茨海默氏病的影响。据报道，其中一些疾病与成年海马神经发生的障碍有关。成人海马神经发生的实验破坏会导致啮齿动物对抗抑郁药/抗焦虑治疗的学习和行为反应缺陷。因此，成人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尚不清楚。我们最近使用一种新型的遗传技术发现，干细胞不仅会根据目前接受的神经元，而且会产生更多的干细胞，这取决于动物的经验和干细胞的位置。我们还开发了一系列环境操作，可以驱动干细胞复制自己，成为神经元。当前建议的目的是利用我们的遗传和行为系统来揭示使成人大脑允许神经发生和干细胞增殖的结构和分子逻辑。在一系列移植中，基因表达分析和电路映射实验，我们打算探索社会环境可以指导移植的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，以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有助于大脑通过增加生命经历变得更加有利时会产生更多神经元的干细胞数量来适应逆境。我们的结果将为探索如何指示现有的干细胞繁殖并在成年大脑中产生更多神经元以改善大脑功能并可能战斗疾病的基础。这些知识还可能有线，以克服非疗法脑结构中对神经发生的抵抗力。公共卫生相关性：成人大脑中基于细胞的疗法的承诺并不是出生的水果，而是积极追求脑部疾病。在这里，研究人员建议利用其技术进步来鉴定局部脑微环境的变化以及干细胞本身的变化，他们本身，指示干细胞增殖或制造神经元，并检查是否可以对这些变化进行选择，以用于大脑中的基于细胞的治疗。最后，研究人员将探索这种“经验指导”的干细胞命运可塑性在适应压力中的作用。