Regulation of Neurogenesis and Cognition by Systemic Age-Related Immune Factors

全身年龄相关免疫因子对神经发生和认知的调节

基本信息

批准号：
8546253
负责人：
SAUL A VILLEDA
金额：
$ 36.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546253
关键词：
Address Adenoviruses Adult Affect Aging Aging-Related Process Alzheimer&apos s Disease Animals Blood Brain CCL11 gene CCL2 gene Cell Culture Techniques Cell Proliferation Cell physiology Cells Coculture Techniques Cognition Cognitive Complement Degenerative Disorder Environment Exposure to Functional disorder Goals Hippocampus (Brain)Immune Impaired cognition Impairment In Vitro Injection of therapeutic agent Laboratories Learning Mediating Memory Methods Microglia Molecular Mus Natural regeneration Nervous system structure Neuraxis Neurodegenerative Disorders Organ Parabiosis Pathway interactions Process Proteins RNA Interference Radial Recombinants Regulation Research Role Signal Transduction Stem cells Testing Therapeutic Tissues Training Viral Virus Water Work adult neurogenesis age effect age related aging brain arm base cell type cognitive function conditioned fear environmental change in vivo interest nerve stem cell neurogenesis normal aging public health relevance receptor receptor expression regenerative relating to nervous system repaired response retroviral-mediated self-renewal stem tissue repair

项目摘要

DESCRIPTION (provided by applicant): Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and amelioration of age-related organ dysfunction. The possibility of harnessing stem cells to reverse normal aging raises the question as to how the aging process modulates tissue specific stem cell activity. In the central nervous system, investigating the effect of aging on neural stem/progenitor cell (NPC) function is of particular interest due to the associated onset of cognitive impairments, and lack of neural repair in response to neurodegenerative diseases, such as Alzheimer's disease. During my doctoral work, I discovered that molecular changes occurring in the aging systemic milieu negatively regulate NPC function and cognition. Furthermore, I identified a subset of systemic immune factors - ¿2-Microglobulin (B2M), CCL11 and CCL2 -, as potential regulators of neurogenesis and cognitive function. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis. Thus, the goal of this application is to investigate how immune-related molecular changes in the aging systemic milieu regulate NPC function and associated cognitive processes. Specifically, my hypothesis is that systemic age-related immune factors impair neurogenesis, and cognitive processes, by both inhibiting NPC function directly and indirectly via resident immune cells. I will address this hypothesis in three aims: 1.To determine the direct versus indirect effect of systemic age-related immune factors on NPC function in vitro, 2. To examine the direct effect of systemic age-related immune factors on neurogenesis and cognitive function in vivo, 3. To explore the indirect effect of systemic age-related immune factors mediated by resident immune cells on neurogenesis and cognitive function in vivo. Ultimately, I hope that by investigating the cellular and molecular mechanisms underlying impairments in NPC function, we can better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity remaining within the old brain.

描述（由申请人提供）：干细胞因其在介导增强组织修复、退行性疾病再生以及改善与年龄相关的器官功能障碍方面的潜力而成为众多科学努力的焦点。利用干细胞逆转正常的可能性。衰老提出了一个问题，即衰老过程如何调节组织特异性干细胞活性。在中枢神经系统中，由于与神经干细胞/祖细胞（NPC）功能相关，因此研究衰老对神经干细胞/祖细胞（NPC）功能的影响特别令人感兴趣。在我的博士研究期间，我发现衰老的系统环境中发生的分子变化会对鼻咽癌功能和认知产生负面影响。免疫因素 - ¿ 2-微球蛋白 (B2M)、CCL11 和 CCL2 - 作为衰老系统环境中神经发生和认知功能的潜在调节剂，可调节 NPC 功能和相关认知过程。具体来说，我的假设是系统性年龄相关免疫。因素通过直接和间接抑制 NPC 功能来损害神经发生和认知过程我将通过三个目标阐述这一假设：1.确定全身年龄相关免疫因素对体外鼻咽癌功能的直接影响和间接影响，2.检查全身年龄相关免疫因素的直接影响。 3. 探讨免疫常驻细胞介导的系统性年龄相关免疫因子对体内神经发生和认知功能的间接影响，最终希望通过研究神经发生和认知功能损伤的细胞和分子机制。 NPC功能，我们可以更好的理解如何通过利用旧大脑中残留的潜在可塑性来改善与年龄相关的认知功能障碍。