Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Promotes Regeneration of Corneal Epithelial Cells via NR4A1 Signaling Pathway
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PROVIDER: PRJNA1226947 | ENA |
REPOSITORIES: ENA
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Project description:Investigation of transcriptional changes induced in adult primary neural stem cells when stimulated with the proliferative agent PACAP (pituitary adenylate cyclase-activating polypeptide). In addition the data was compared to results obtained from a proliferation control (stimulation with a transmembrane receptor agonist) and a differentiation control (primary neural stem cells induced to differentiate by withdrawing growth factors, adding serum and plating onto solid support).
2005-05-15 | E-MEXP-322 | biostudies-arrayexpress
Project description:PACAP is a neuropeptide that promotes lacrimal fluid secretion, but its direct action on corneal injury remains to be clarified. Therefore, the effect of PACAP on corneal epithelial repair was clarified using mouse corneal wound-injury model and human corneal epithelial culture cells. PAC1-R mRNA and its immunoreactivity was detected in mouse and corneal epithelium. In corneal wound-injury model mice, PACAP eye drop significantly reduced the injured area at 12 hours, and the effect was cancelled by co-treatment with the PACAP receptor antagonist. PACAP heterozygous and PAC1-R knockout mouse delayed the corneal healing. Although surgical removal of the lacrimal gland attenuates corneal healing, PACAP eye drop on the eyes significantly recuperated corneal damage. In an in-vitro study, PACAP treatment in human corneal epithelial cells significantly decreased the injury area induced by scratching. PACAP treatment in the in-vitro human corneal epithelial cell experiments significantly reduced the area of injury and abolished the corneal repair effect due to the inhibitory effect of Ara-C on proliferation. DNA whole-genome microarray analysis suggested that the nuclear receptor NR4A1 is an important factor in corneal epithelial proliferation, and THPN, which induces nuclear export of NR4A1, suppressed PACAP-induced proliferation of human corneal epithelial cells and the repair effect of mouse corneal epithelium. These data suggest that PACAP stimulates corneal repair by corneal epithelial proliferation via PAC1-R and NR4A1 transcriptional activity. PACAP could be a good candidate as an eye-drop medication for corneal injury disease including dry eye syndrome.
2025-02-27 | GSE290267 | GEO
Project description:Mucosal healing remains a pivotal therapeutic endpoint in ulcerative colitis (UC) management, yet cellular mechanisms driving tissue repair remain elusive. Here we demonstrate that Pirt+ nociceptor endings dynamically grow into the granulation tissue during colonic mucosal restitution, releasing pituitary adenylate cyclase-activating polypeptide (PACAP) to orchestrate reparative processes. Absence of PACAP signaling in Pirt+ sensory neurons resulted in delayed healing, while exogenous PACAP administration accelerated mucosal restitution in experimental colitis models. Mechanistically, PACAP exerts its pro-reparative effects through vasoactive intestinal peptide receptor 2 (VIPR2), with pituitary adenylate cyclase-activating polypeptide receptor type 1 and vasoactive intestinal peptide receptor 1 playing negligible roles in this context. Mouse and human fibroblast expressed VIPR2. VIPR2+ fibroblasts increased during mucosal healing and accumulated in granulation tissue. Conditional deletion of VIPR2 in fibroblasts abolished PACAP-mediated tissue repair. The effects of PACAP on mucosal healing are mediated via interleukin-11 released by VIPR2+ fibroblast. Our findings demonstrate a neuron-fibroblast axis that orchestrates mucosal healing, highlighting its therapeutic potential as a novel target for UC management.
2025-07-16 | GSE302394 | GEO
Project description:Sweat has a critical role in human body, including thermoregulation and maintenance of skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion resulting in severe skin conditions (pruritus and erythema). Bioactive peptide, pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. In recent years, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intercellular [Ca2+] via PAC1R in NCL-SG3 cells. However, the intracellular signaling mechanisms by PACAP are poorly clarified. In this study, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat gland by PACAP treatment. Immunohistochemistry revealed that PACAP promotes the translocation of AQP5 to lumen side in eccrine gland via PAC1R. Furthermore, PACAP up-regulates gene expression (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Further, PACAP treatment down-regulated Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Overall our data provide a solid basis for future research initiatives to develop new therapies to treat sweating disorders.
2023-01-23 | GSE223124 | GEO
Project description:New neurons are born throughout the life of mammals in germinal zones of the brain known as neurogenic niches: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. These niches contain a subpopulation of cells known as adult neural progenitors (aNPCs), which self-renew and give rise to new neurons and glia. aNPCs are regulated by many factors present in the niche, including the extracellular matrix (ECM). We show that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) affects subventricular zone-derived aNPCs by increasing their surface adhesion. Gene array and reconstitution assays indicate that this effect can be attributed to the regulation of ECM components and ECM-modifying enzymes in aNPCs by PACAP. Our work suggests that PACAP regulates a bidirectional interaction between the aNPCs and their niche: PACAP modifies ECM production and remodeling, in turn the ECM regulates progenitor cell adherence. We speculate that PACAP may in this manner help restrict adult neural progenitors to the stem cell niche in vivo, with potential significance for aNPC function in physiological and pathological states.
2017-02-01 | GSE66193 | GEO
Project description:Recently, our group has shown that the pituitary adenylate cyclase-activating polypeptide (PACAP)-induced neurite projection elongation in rat adrenal-derived pheochromocytoma cell line (PC12) is mediated via PAC1 receptor-mediated dephosphorylation of CRMP2 majorly through PI3K/AKT and MEK/ERK pathways. However, the mechanism of neuronal outgrowth by PACAP, including CRMP2 dephosphorylation, remains unclear. In our previous report, we found that GSK-3β, CDK5, and Rho/ROCK dephosphorylated CRMP2 within 3 hours after the addition of PACAP, but the early dephosphorylation of CRMP2 by PACAP remains unclear. Thus, we considered it important to identify early factors in PACAP-induced neurite projection elongation and performed omics-based transcriptomic (whole genome DNA microarray) and proteomic (TMT-labeling in conjunction with liquid chromatography-tandem mass spectrometry) analyses of gene and protein expression profiles from 5-120 minutes after PACAP addition. Results surprisingly revealed a number of key regulators involved in neurite outgrowth, including known ones. We also identified factors that may be involved in CRMP2 dephosphorylation. Cross-referencing previous research, we tried to map these molecular components onto potential pathways. The results of this comprehensive analysis may provide important new information on the molecular mechanisms of neuronal differentiation induced by PACAP.
2023-01-25 | GSE223333 | GEO
Project description:Recently, our group has shown that the pituitary adenylate cyclase-activating polypeptide (PACAP)-induced neurite projection elongation in rat adrenal-derived pheochromocytoma cell line (PC12) is mediated via PAC1 receptor-mediated dephosphorylation of CRMP2 majorly through PI3K/AKT and MEK/ERK pathways. However, the mechanism of neuronal outgrowth by PACAP, including CRMP2 dephosphorylation, remains unclear. In our previous report, we found that GSK-3β, CDK5, and Rho/ROCK dephosphorylated CRMP2 within 3 hours after the addition of PACAP, but the early dephosphorylation of CRMP2 by PACAP remains unclear. Thus, we considered it important to identify early factors in PACAP-induced neurite projection elongation and performed omics-based transcriptomic (whole genome DNA microarray) and proteomic (TMT-labeling in conjunction with liquid chromatography-tandem mass spectrometry) analyses of gene and protein expression profiles from 5-120 minutes after PACAP addition. Results surprisingly revealed a number of key regulators involved in neurite outgrowth, including known ones. We also identified factors that may be involved in CRMP2 dephosphorylation. Cross-referencing previous research, we tried to map these molecular components onto potential pathways. The results of this comprehensive analysis may provide important new information on the molecular mechanisms of neuronal differentiation induced by PACAP.
2023-03-11 | PXD039992 | Pride
Project description:Stressor exposure is associated with the onset and severity of many psychopathologies that are more common in women than men. Moreover, the maladaptive expression and function of stress-related hormones have been implicated in these disorders. Evidence suggests that PACAP has a critical role in the stress circuits mediating stress-responding, and PACAP may interact with sex hormones to contribute to sex differences in stress-related disease. In this review, we describe the role of the PACAP/PAC1 system in stress biology, focusing on the role of stress-induced alterations in PACAP expression and signaling in the development of stress-induced behavioral change. Additionally, we present more recent data suggesting potential interactions between stress, PACAP, and circulating estradiol in pathological states, including PTSD. These studies suggest that the level of stress and circulating gonadal hormones may differentially regulate the PACAPergic system in males and females to influence anxiety-like behavior and may be one mechanism underlying the discrepancies in human psychiatric disorders.
| S-EPMC6724739 | biostudies-literature
Project description:Corynebacterium glutamicum GlxR suppressor mutant of adenylate cyclase (cyaB) deletion strain
| PRJEB36438 | ENA
Project description:The bovine chromaffin cell (BCC) is a unique model—a highly homogeneous and accessible neuroendocrine cell—in which to study gene regulation through first messenger-initiated signaling pathways that are specific to post-mitotic cells. BCCs were treated with tumor necrosis factor (TNF) or pituitary adenylate cyclase activating polypeptide (PACAP), two critical regulators of neural cell transcriptional programming during inflammation that act on TNFR2 and PAC1 receptors, respectively, in post-mitotic neuroendocrine cells. Transcripts which were significantly up regulated by either or both first messenger were identified from microarray analysis using two bovine oligonucleotide arrays (Affymetrix and Agilent) followed by statistical analysis with Partek Genomic suite. Microarray data were combined from the two arrays using qRT-PCR sampling validation, and the first-messenger transcriptome derived from TNF and PACAP signaling were compared. More than 90 percent of the genes up regulated either by TNF or PACAP were specific to a single first messenger. BioBase suite, DIRE and Opossum were used to identify common promoter/enhancer response elements that control the expression of TNF- or PACAP-stimulated genes. Bioinformatic analysis revealed that distinct groups of transcription factors control the expression of genes up regulated by either TNF or PACAP . Most of the genes up regulated by TNF contained response elements for members of the Rel transcription factor family, suggesting TNF-TNFR2 signaling mainly through the NF-kB signaling pathway. On the other hand, the PACAP regulated genes showed no enrichment for any single response element, containing instead response elements for combinations of transcription factors allowing activation through multiple signaling pathways, including cAMP, calcium and ERK, in neuroendocrine cells. Pharmacological strategies for mimicking neuroprotection by either PACAP or TNF in the context of CNS injury or degeneration in disease might focus on individual downstream gene activation pathways to achieve greater specificity in vivo.
2012-09-01 | GSE24070 | GEO