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

• 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
• 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' 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

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，破坏家庭稳定，并导致多年的工作生产力损失，使其成为世界上最昂贵的疾病。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抗性，需要新的治疗方法，并且不存在广泛接受的对自闭症有效的治疗。三十多年来，将培养的神经细胞注射到受疾病影响的大脑区域的治疗尝试产生了令人失望的结果。最近使用干细胞进行细胞治疗的可能性是有趣的，因为干细胞具有成为神经元和其他细胞的潜力（多能性）。然而，指导干细胞成为神经元的细胞和分子信号仍然难以捉摸。 移植治疗成功率有限的一个原因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。在这两个允许的结构中，海马体受到抑郁症、焦虑症、精神分裂症、自闭症和阿尔茨海默病的影响。据报道，这些疾病中有几种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动物对抗抑郁/抗焦虑治疗的学习和行为反应的缺陷。因此，成年大脑中的海马神经发生可能参与疾病状态。成人大脑中允许神经发生的细胞和分子事件仍然未知。 利用一种新的遗传技术，我们最近发现，干细胞不仅能产生目前公认的神经元，而且还能产生更多的干细胞，这取决于动物的经历和干细胞的位置。我们还开发了一系列的环境操作，可以驱动干细胞复制自己，成为神经元。目前的建议的目标是利用我们的遗传和行为系统来揭示结构和分子逻辑，使神经发生和干细胞增殖在成人大脑中是允许的。在一系列的移植，基因表达分析，电路映射实验，我们打算探索的机制，社会环境可以直接移植的干细胞增殖，并成为神经元。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。我还将探索这种对环境变化的反应是否有助于大脑适应逆境，因为当生活经历变得更有利时，干细胞的数量会增加，从而产生更多的神经元。我们的研究结果将为探索如何指导现有的干细胞在成人大脑中繁殖和产生更多的神经元以改善大脑功能并可能对抗疾病奠定基础。这一知识也可能为克服非允许性大脑结构中神经发生的阻力提供线索。 公共卫生相关性：在成人大脑中进行基于细胞的治疗的承诺尚未取得成果，但正在积极寻求治疗大脑疾病。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，这些变化指示干细胞增殖或制造神经元，并检查这些变化是否可以用于大脑中基于细胞的治疗。最后，研究人员将探索这种“经验导向”的干细胞命运可塑性在适应压力中发挥的作用。