FUNCTIONS OF PACAP IN OLFACTORY NEURONS

PACAP 在嗅觉神经元中的功能

• 批准号: 6986115
• 负责人: MARY T LUCERO
• 金额: $ 32.12万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986115
• 关键词: adenylate cyclase; apoptosis; biological signal transduction; cell differentiation; chemoreceptors; cytokine; electrophysiology; experimental brain lesion; gene expression profiling; genetically modified animals; laboratory mouse; nervous system regeneration; neurogenesis; neurons; neuropeptide receptor; neuropeptides; olfactions; olfactory lobe; protein isoforms; receptor expression; respiratory epithelium

DESCRIPTION (provided by applicant): The sensation of smell enables us to gain valuable information about a plethora of chemicals in our immediate environment, and to respond appropriately. Olfactory receptor neurons (ORNs) are responsible for detection of these chemicals and are unique among neurons because following death due to cytotoxic insults or viral infections, they are replaced by new ORNs. This process occurs in the olfactory epithelium (OE) lining the nose and involves the step-wise transformation of mitotic basal ("stem") cells into differentiated mature ORNs. In experiments outlined in this application, we will investigate the role of pituitary adenylate cyclase activating peptide (PACAP) in proliferation and maturation of normal developing and regenerating OE. PACAP is an intraepithelial peptide that acts as a cue for the regeneration of ORNs and for initiating defensive responses within ORNs to minimize cell death or apoptosis. The interaction of the signaling pathways activated by cell-extrinsic PACAP and cell-intrinsic electrical activity of ORNs in promoting differentiation of progenitor cells into differentiated ORNs will be investigated. In three specific aims, we will determine: (1) the expression profiles of PACAP and isoforms of its receptor (PAC1) in the developing and adult OE of wild-type and PACAP ko mice with and without bulb ablation; (2) the contributions of PACAP and cell-intrinsic activity in driving the maturation of ORNs and proliferation of basal stem cells, and (3) how PACAP prevents apoptosis of ORNs following cytokine inundation of the OE and injury caused by bulb ablation. Our studies are timely and critical for gaining an understanding of the cellular and signaling mechanisms involved in neuroregeneration in general, and are directly relevant to addressing the causes and potentials remedies of neurodegenerative diseases such as Alzheimer's and Parkinson's disease in which olfactory dysfunction is an early symptom.

描述(申请人提供)：嗅觉使我们能够获得关于我们周围环境中过多化学物质的有价值的信息，并做出适当的反应。嗅觉感受器神经元负责检测这些化学物质，在神经元中是独一无二的，因为在由于细胞毒性侮辱或病毒感染而死亡后，它们会被新的嗅觉感受器神经元取代。这一过程发生在鼻腔衬里的嗅觉上皮(OE)，并涉及有丝分裂的基底层(“干细胞”)细胞逐步转化为分化的成熟On。在本应用概述的实验中，我们将研究垂体腺苷酸环化酶激活肽(PACAP)在正常发育和再生OE的增殖和成熟中的作用。PACAP是一种上皮内肽，可作为ON再生的信号，并在ON内启动防御反应，将细胞死亡或凋亡降至最低。我们将研究细胞-外源性PACAP激活的信号通路与Orns细胞内的电活动在促进前体细胞向分化的Orn分化过程中的相互作用。在三个特定的目标中，我们将确定：(1)PACAP及其受体(PAC1)在野生型和PACAP Ko小鼠发育和成体OE中的表达谱；(2)PACAP和细胞固有活性在推动ON成熟和基础干细胞增殖中的作用；以及(3)PACAP如何防止OE细胞因子淹没后ON的凋亡和球茎切除所造成的损伤。我们的研究对于了解神经再生所涉及的细胞和信号机制是及时和关键的，并与解决神经退行性疾病的原因和潜在的治疗方法直接相关，例如阿尔茨海默氏症和帕金森氏病，在这些疾病中，嗅觉功能障碍是早期症状。