RAGE AND NERVE INJURY, REGENERATION, DIABETES AND AGING

愤怒和神经损伤、再生、糖尿病和衰老

基本信息

批准号：
8092693
负责人：
ANN MARIE SCHMIDT
金额：
$ 33.19万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8092693
关键词：
Acute Address Advanced Glycosylation End Products Affect Age Aging Alzheimer&apos s Disease Attenuated Autonomic nervous system Blocking Antibodies Blood Vessels Cell physiology Cells Cellular Stress Cessation of life Chronic Chronic stress Clinic Clinical Trials Collaborations Complement Complications of Diabetes Mellitus Crush Injury Cutaneous Deposition Development Diabetes Mellitus Diabetic Neuropathies Diabetic mouse Disease Progression Distal Dominant-Negative Mutation Environment Exposure to Fostering Functional disorder Gene Expression Generations Genetic Glucose HMGB1 Protein Homeostasis Hyperglycemia In Vitro Incidence Inflammation Inflammatory Inflammatory Response Injury Insulin Resistance Kidney Knockout Mice Lead Life Ligand Binding Domain Ligands Ligation Link Lipids Modification Molecular Mononuclear Mus Natural regeneration Nerve Nerve Crush Nerve Degeneration Nerve Regeneration Nervous system structure Neurites Neuronal Dysfunction Neurons Neuropathy Obesity Pathway interactions Periodontium Peripheral Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Peripheral nerve injury Phagocytes Positioning Attribute Process Property Proteins Publishing Rage Reagent Regulation Rodent Model Role Signal Transduction Site Spinal Ganglia Streptozocin Stress Structure Testing Therapeutic Time Tissues Transcription factor genes Transgenic Mice Transgenic Organisms Up-Regulation Wallerian Degeneration Work acute stress axon regeneration base cell type diabetic extracellular glycation human subject in vivo insight mutant nerve injury non-diabetic oxidation programs promoter receptor receptor for advanced glycation endproducts regenerative reinnervation repaired response scavenger receptor sciatic nerve sensory neuropathy small molecule transcription factor

项目摘要

Aging and diabetes are associated with increased generation and deposition of Advanced Glycation Endproducts, or AGEs, the products of nonenzymatic glycation/oxidation of proteins/lipids. As human subjects age, the incidence of insulin resistance and, often, frank hyperglycemia rises. Long-lived proteins of the peripheral nervous system (PNS) are highly susceptible to AGE modification. AGEs, an heterogeneous class of molecules, may modify cellular function by an array of distinct mechanisms. One such mechanism is by their ligation of the signal transduction receptor, RAGE. RAGE also interacts with S100/calgranulins and amphoterin (or high mobility box group 1, HGMB1), which display diverse functions, such as neurite outgrowth and inflammation. Among the complications of diabetes, symmetrical neuropathy of the sensory and autonomic nervous systems affects significant numbers of diabetic subjects. Evidence accrued from the first five years of this Project has suggested an innate, survival role for RAGE in response to acute peripheral nerve injury. In euglycemia, transient and sharply-limited upregulation of RAGE (particularly in mononuclear phagocytes [MP] and neuronal/axonal structures) and its ligands is linked to RAGE-dependent inflammation and neurite outgrowth that contribute beneficially to regeneration. In diabetes, regeneration consequent to acute injury, such as crush, is significantly impaired. We hypothesize that in diabetes, chronic and sustained accumulation of AGEs and RAGE ligands, and upregulation of RAGE, perturbs homeostatic mechanisms in the peripheral nerve, leading to chronic dysfunction. Upon superimposed acute nerve injury, RAGE-dependent mechanisms sustain inflammation and neuronal dysfunction, and thwart regeneration. This proposal will address the fundamental question of whether RAGE/RAGE signaling globally, or specifically in cells of MP lineage or neurons, is protective or destructive to peripheral neurons in diabetes. We propose that in euglycemia, acute engagement of RAGE/RAGE signaling in both cell types is protective for peripheral neurons, but that chronic activation in diabetes promotes long-term neuronal dysfunction in the absence or presence of superimposed acute injury. This Project is critically linked to Project 1, as studies in chronic AB-enrichment in the CMSstrongly support deleterious and maladaptive roles for RAGE in neuronal stress. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes, it is imperative to dissect the beneficial vs maladaptive impact of RAGE in both the CMS and PNS, and in chronic stress vs acute injury. Projects 1 and 2 are uniquely positioned to address these questions due to the long-time collaboration of the leaders of these Projects. Project 2 will employ Cores A and B through all five years of this Program.

衰老和糖尿病与晚期糖基化的产生和沉积增加有关最终产物或年龄，是蛋白质/脂质非酶糖化/氧化的产物。作为人类受试者年龄，胰岛素抵抗的发生率以及弗兰克高血糖的升高。长寿命的蛋白质周围神经系统（PNS）高度容易受到年龄的改变。年龄，一个异质分子类别可以通过一系列不同的机制来改变细胞功能。一种这样的机制是通过连接信号转导受体的愤怒。愤怒也与S100/calgranulins相互作用和大苯林（或高移动框组1，HGMB1），它们显示多种功能，例如神经突产物和炎症。在糖尿病的并发症中，感觉的对称神经病自主神经系统会影响大量糖尿病患者。从该项目的头五年提出了对急性周围的愤怒的先天生存作用神经损伤。在尤利西亚（Euglycemia 吞噬细胞[MP]和神经元/轴突结构）及其配体与依赖愤怒的炎症有关和神经突生长，对再生有利贡献。在糖尿病中，再生急性损伤（例如粉碎）受到明显的损害。我们假设在糖尿病，慢性和年龄和愤怒配体的持续积累，以及愤怒的上调周围神经的机制，导致慢性功能障碍。叠加急性神经损伤后，依赖愤怒的机制具有炎症和神经元功能障碍，并阻碍了再生。该建议将解决全球愤怒/愤怒信号的基本问题，还是特别是在MP谱系或神经元细胞中，对糖尿病的周围神经元具有保护性或破坏性。我们提出，在尤利克米亚中，两种细胞类型中的愤怒/愤怒信号的急性参与是保护性的对于周围神经元，但糖尿病中的慢性激活促进了长期神经元功能障碍不存在或存在叠加急性损伤。该项目与项目1密切相关，作为研究 CMSStrongly支持有害和适应不良的角色的慢性AB-在神经元中的愤怒压力。随着愤怒的对抗接近阿尔茨海默氏病和糖尿病的临床试验，必须必须剖析愤怒对CM和PN的有益与适应不良的影响，以及在慢性应激中急性损伤。由于长期以来，项目1和2的位置是独特的，可以解决这些问题这些项目领导者的合作。项目2将在整个五年内采用核心A和B 这个程序。