Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

胃肠肽/生长因子作用的细胞基础

基本信息

批准号：
10493931
负责人：
Robert Jensen
金额：
$ 85.49万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/10493931
关键词：
Area Bombesin Bombesin Receptor Cell physiology Cells ERBB2 gene ERBB3 gene Endothelin Endothelin Receptor Epidermal Growth Factor Receptor Family Family member G-Protein-Coupled Receptors Gastrointestinal Hormones Gastrointestinal tract structure Growth Growth Factor Growth Factor Receptors Hormones Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Neuraxis Neuropeptides Neurotensin Neurotransmitters Paper Pathologic Processes Peptides Physiological Process Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Receptor Protein-Tyrosine Kinases Reporting Role Serine/Threonine Phosphorylation Signal Transduction Therapeutic Tissues Transactivation Tyrosine Tyrosine Phosphorylation Vasoactive Intestinal Peptide Receptors base cell growth cell motility dimer gastrointestinal human disease lung cancer cell neoplastic novel novel therapeutic intervention pituitary adenylate cyclase activating polypeptide receptor tumor growth tyrosine receptor

项目摘要

During the year we have written a number of invited reviews and critical analyses which are partially based on our studies of the cellular basis of action of various gastrointestinal peptides (bombesin receptor family, VIP-PACAP peptide family, endothelin receptor family, neurotensin. These include papers reporting the effects of activation of a number of these receptors on cancer growth through the transactivation of the EGF receptor family as well as reviews of the possible therapeutic roles of PACAP/VIP and bombesin receptor families in various human diseases and CNS cancers, respectively. Recent studies show that in both normal and neoplastic tissues, gastrointestinal hormones (GI) and GI growth factors (GF) may cause cell growth by stimulating multiple intracellular tyrosine/serine/threonine phosphorylation (TyrP) signaling cascades as well as by transactivation of growth factor receptors. However, at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. In a study this year we report that the neuropeptide, PACAP in lung cancer cells stimulates growth of these tumors while signaling principally by transactivation of a number of EGFR family members including EGFR, HER2 and HER3. In these cells PACAP stimulated the formation of EGFR/HER3 and HER2/HER3 dimers resulting in proliferation. Recent studies, including ours have demonstrated that in different cells the mechanisms of the ability of these peptides to stimulate tyrosine phosphorylation and receptor tyrosine kinases involves a number of different mechanisms, and this was reviewed in detail for PACAP-VIP, Bombesin, endothelin and neurotensin in an invited review this year. The novel abilities of these GPCRs to activate these tyrosine kinase cascades are demonstrating the importance of these receptors in numerous physiological/pathological processes, particular growth cascades of both normal and cancer tissues, opening new therapeutic approaches.

在这一年中，我们撰写了许多受邀评论和批判性分析，部分基于我们对各种胃肠肽（铃蟾肽受体家族、VIP-PACAP 肽家族、内皮素受体家族、神经降压素）作用的细胞基础的研究。这些包括论文报道了通过 EGF 受体家族的反式激活激活许多此类受体对癌症生长的影响，以及对 PACAP/VIP 和铃蟾肽受体家族在各种人类疾病和中枢神经系统中可能的治疗作用的评论分别是癌症。最近的研究表明，在正常和肿瘤组织中，胃肠激素（GI）和胃肠道生长因子（GF）可能通过刺激多个细胞内酪氨酸/丝氨酸/苏氨酸磷酸化（TyrP）信号级联以及生长因子的反式激活来引起细胞生长受体。然而，目前对许多胃肠激素/生长因子激活这些级联的能力知之甚少。在今年的一项研究中，我们报告肺癌细胞中的神经肽 PACAP 刺激这些肿瘤的生长，同时主要通过包括 EGFR、HER2 和 HER3 在内的许多 EGFR 家族成员的反式激活来发出信号。在这些细胞中，PACAP 刺激 EGFR/HER3 和 HER2/HER3 二聚体的形成，从而导致增殖。最近的研究（包括我们的研究）表明，在不同的细胞中，这些肽刺激酪氨酸磷酸化和受体酪氨酸激酶的能力机制涉及许多不同的机制，并且对 PACAP-VIP、Bombesin、内皮素和神经降压素进行了详细回顾在今年的邀请评审中。这些 GPCR 激活这些酪氨酸激酶级联的新能力证明了这些受体在许多生理/病理过程中的重要性，特别是正常组织和癌症组织的生长级联，开辟了新的治疗方法。