Neurobiological Basis of Neuronal Survival

神经元存活的神经生物学基础

• 批准号: 10267541
• 负责人: Tsung-Ping Ping Su
• 金额: $ 80.8万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267541
• 关键词: Affect; Astrocytes; Brain; Brain Injuries; Cell Survival; Complement 1q; Conditioned Culture Media; Disease; Gene Expression; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hippocampus (Brain); Knock-out; Knockout Mice; Learning; Lipids; Memory; Mental disorders; Metabolism; Morphology; Neurites; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurons; Pathologic; Poison; Proteins; Role; Signal Transduction; Stress; TLR2 gene; Therapeutic Agents; conditional knockout; design; injury prevention; motor behavior; neurobiological mechanism; neuron development; neuronal survival; receptor function; sigma-1 receptor; synaptogenesis

Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. Sigma-1 receptor relates to Sp1 signaling. In this year, we found that Sp1 was highly expressed in astrocytes, implying that Sp1 might be important for the function of astrocytes. Sp1/GFAP-Cre-ERT2 conditional knockout mice were constructed to study the role of Sp1 in astrocytes. Knockout of Sp1 in astrocytes altered astrocytic morphology and decreased GFAP expression in the cortex and hippocampus but did not affect cell viability. Loss of Sp1 in astrocytes decreased the number of neurons in the cortex and hippocampus. Conditioned medium from primary astrocytes with Sp1 knockout disrupted neuronal dendritic outgrowth and synapse formation, resulting in abnormal learning, memory, and motor behavior. Sp1 knockout in astrocytes altered gene expression, including decreasing the expression of Toll-like receptor 2 and Cfb and increasing the expression of C1q and C4Bp, thereby affecting neurite outgrowth and synapse formation, resulting in disordered neuron function. Studying these gene regulations might be beneficial to understanding neuronal development and brain injury prevention.

Sigma-1 受体 (Sig-1R) 作为伴侣与多种蛋白质和脂质相互作用，与神经退行性疾病和精神疾病有关。 Sigma-1 受体与 Sp1 信号传导相关。 今年，我们发现Sp1在星形胶质细胞中高表达，这意味着Sp1可能对星形胶质细胞的功能很重要。构建Sp1/GFAP-Cre-ERT2条件敲除小鼠来研究Sp1在星形胶质细胞中的作用。星形胶质细胞中 Sp1 的敲除改变了星形胶质细胞的形态并降低了皮质和海马中的 GFAP 表达，但不影响细胞活力。星形胶质细胞中 Sp1 的缺失会减少皮质和海马体中神经元的数量。 Sp1 敲除的原代星形胶质细胞的条件培养基破坏了神经元树突生长和突触形成，导致学习、记忆和运动行为异常。星形胶质细胞中的 Sp1 敲除改变了基因表达，包括减少 Toll 样受体 2 和 Cfb 的表达，增加 C1q 和 C4Bp 的表达，从而影响神经突生长和突触形成，导致神经元功能紊乱。研究这些基因调控可能有助于了解神经元发育和脑损伤预防。