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: 8004856
• 负责人: ALEX DRANOVSKY
• 金额: $ 41.39万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004856
• 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，会破坏家庭的稳定，并导致多年的工作效率下降，使它们成为世界上最昂贵的疾病。虽然有一些治疗抑郁症和精神分裂症的好方法，但许多患者对治疗有抵抗力，需要新的治疗方法，而且目前还没有被广泛接受的治疗自闭症的有效方法。30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基础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（多能性）的潜力。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。在这两种容许性结构中，海马体受抑郁、焦虑、精神分裂症、自闭症和阿尔茨海默病的影响。据报道，其中一些疾病与成人海马神经发生障碍有关。实验性破坏成年海马神经发生导致啮齿动物对抗抑郁/抗焦虑治疗的学习和行为反应缺陷。因此，成人大脑海马神经发生可能参与疾病状态。允许成人大脑神经发生的细胞和分子事件仍然未知。利用一种新的基因技术，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，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，可以驱动干细胞自我复制，成为神经元。目前这项研究的目标是利用我们的遗传和行为系统来揭示成人大脑中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定位实验中，我们打算探索社会环境如何指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历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。我还将探索这种对环境变化的反应是否有助于大脑适应逆境，通过增加干细胞的数量，当生活经历变得更有利时，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导现有的干细胞在成人大脑中繁殖和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。这一知识也可能为克服非允许大脑结构中神经发生的阻力提供线索。