FUNCTIONS OF PACAP IN OLFACTORY NEURONS

描述（由申请人提供）：嗅觉使我们能够获得有关我们周围环境中过多化学物质的有价值信息，并做出适当反应。嗅觉受体神经元（ORN）负责检测这些化学物质，并且在神经元中是独特的，因为在由于细胞毒性损伤或病毒感染而死亡后，它们被新的ORN取代。这个过程发生在鼻子的嗅上皮（OE）中，涉及有丝分裂的基底（“干”）细胞逐步转化为分化的成熟ORN。在本申请中概述的实验中，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. PACAP的增殖和成熟中的作用。PACAP是一种上皮内肽，作为一种线索，为ORN的再生和启动防御反应内ORN，以尽量减少细胞死亡或凋亡。将研究由细胞-外源性PACAP激活的信号通路和ORN的细胞-内源性电活性在促进祖细胞分化为分化的ORN中的相互作用。本研究的目的有三：（1）PACAP及其受体（PAC 1）在野生型和PACAP ko小鼠发育和成年OE中的表达谱;（2）PACAP和细胞内在活性在驱动ORN成熟和基底干细胞增殖中的作用，以及（3）PACAP如何防止OE的细胞因子淹没和灯泡消融引起的损伤后的ORN凋亡。我们的研究对于了解神经再生中涉及的细胞和信号传导机制是及时和关键的，并且与解决神经退行性疾病的原因和潜在补救措施直接相关，如阿尔茨海默氏症和帕金森氏症，其中嗅觉功能障碍是早期症状。

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.