Anatomy of neuroendocrine peptide pathways in brain

大脑神经内分泌肽通路的解剖

• 批准号: 7429660
• 负责人: Paul E. Sawchenko
• 金额: $ 23.72万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429660
• 关键词: Ablation; Acute; Adrenal Glands; Anatomy; Anorexia Nervosa; Autoimmune Diseases; Behavioral; Binding; Binding Proteins; Brain; Cells; Cereals; Condition; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dependence; Electron Microscopy; Electrons; Elements; Emotional; Endocrine; Etiology; Failure; Family; Functional disorder; Genetic; Goals; Hypertension; Injection of therapeutic agent; Knock-out; Learning; Ligands; Light; Link; Location; Major Depressive Disorder; Mammals; Mediating; Membrane; Memory; Methods; Microscopic; Molecular Target; Mood Disorders; Mus; Mutant Strains Mice; Neurobiology; Neurosecretory Systems; Pathology; Pathway interactions; Peptides; Physiological; Pituitary Gland; Play; Process; RNA Splicing; Range; Role; Signal Transduction; Signaling Molecule; Site; Stress; Structure; Support Groups; System; Testing; Thinking; Time; Upper arm; Ursidae Family; Variant; Work; age related; base; biological adaptation to stress; genetic manipulation; inhibitor/antagonist; mouse model; mutant; novel; programs; receptor; receptor expression; response; stressor; urocortin

The corticotropin-releasing factor (CRF) family of signaling molecules comprises four ligands (CRF, and urocortins (Ucns) 1-3), two receptors (CRFR1 and -R2) and a binding protein (CRFBP). This family is thought to play critical and interactive roles in the integration of endocrine, autonomic and behavioral responses to stress. An interconnected network of brain structures, termed the central autonomic system (CAS), harbors sensitive sites of stress-related CRF/Ucn action, but its components are generally lacking or impoverished in relevant ligand and/or receptor expression. Our goal is to clarify the functional anatomical organization that provides for generalized stress-induced CAS activation, by ascertaining the disposition and role of specific signaling molecules in specific locations that provide for recruitment of this circuitry in a range of challenge paradigms. Immunolocalization methods will be used at the light and electron microscopic levels to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. We will work with other components of the program to pursue evidence of a novel CRFR enriched in CAS, and if successful, determine its distribution and role in CAS circuitry. Histochemical and anatomical methods will be used to identify molecular targets and sites within the CAS at which CRFR1 and R2 mechanisms interact to sculpt stress responses, and to identify the underlying circuitry. Pharmacologic manipulations in genetically manipulated mouse models will be used to pursue indications of an unexpected role for the CRFBP in signaling in the CAS. Anatomical and functional studies will seek to provide a context for a newly discovered soluble CRFR2 variant. Finally, we will explore a range of possible explanations for the failure of recently discovered CRFR2-selective ligands, Ucn 2 and 3, to activate sites of cognate receptor expression. We will compare the extent to which Ucn 1, 2 and 3-expressing cell groups may be differentially responsive to a range of challenge paradigms, and employ null mutant lines to probe the roles of each peptide system in CAS responses to stress. The CMS systems under scrutiny here play essential physiologic roles in stress adaptation, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age-related deficits in learning and memory, and have been implicated in the etiology of a range of affective disorders, including anorexia nervosa and major depression.

促肾上腺皮质激素释放因子（CRF）家族的信号分子包括四种配体（CRF和尿皮质素（Ucns）1-3）、两种受体（CRFR 1和-R2）和结合蛋白（CRFBP）。该家族被认为在整合内分泌、自主神经和行为对压力的反应中起着关键和相互作用的作用。大脑结构的互连网络，称为中央自主神经系统（CAS），窝藏应激相关的CRF/UCN行动的敏感位点，但其组件通常缺乏或贫困的相关配体和/或受体的表达。我们的目标是通过确定CAS的分布， 特定信号分子在特定位置的作用，在一系列挑战范例中提供该回路的募集。将在光镜和电子显微镜水平上使用免疫定位方法，以确定CRFR如何分布在CAS组分中，以及它们与含配体的末端区域的关系。我们将与该计划的其他组成部分合作，寻求一种富含CAS的新型CRFR的证据，如果成功，确定其在CAS电路中的分布和作用。组织化学和解剖学方法将用于确定CAS内的分子靶点和位点，在这些位点上CRFR 1和R2机制相互作用以塑造应激反应，并确定潜在的电路。在基因操作的小鼠模型中的药理学操作将用于寻找非预期的 CRFBP在CAS中的信号传导中的作用。解剖学和功能研究将寻求为新发现的可溶性CRFR 2变体提供背景。最后，我们将探讨一系列可能的解释失败的最近发现的CRFR 2-选择性配体，UCN 2和3，激活同源受体表达的网站。我们将比较Ucn 1，2和3表达细胞群的程度可能是不同的响应范围内的挑战范例，并采用无效突变株系来探测每个肽系统在CAS应激反应中的作用。CMS系统在这里审查发挥重要的生理作用，在压力适应，功能障碍已被链接到这样的不同的病理学，如自身免疫性疾病，高血压和年龄相关的学习和记忆缺陷，并已牵连在一系列的情感障碍，包括神经性厌食症和抑郁症的病因。