Recovery of Function Following Neural Damage

神经损伤后功能的恢复

• 批准号: 7667376
• 负责人: RICHARD E ZIGMOND
• 金额: $ 31.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667376
• 关键词: Adult; Adverse effects; Aging; Amines; Animals; Antibodies; Architecture; Axon; Axotomy; Belief; Biological; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Cells; Clinical; Cyclic AMP; Defect; Degenerative Disorder; Diabetes Mellitus; Disease; Environment; Failure; Gene Expression; Genes; Grant; Growth; Immune Sera; In Vitro; Injection of therapeutic agent; Injury; Knowledge; Laboratories; Lesion; Measures; Mediating; Medical; Methods; Molecular; Motor; Motor Neurons; Mus; Natural regeneration; Nature; Nerve; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Nervous system structure; Neuraxis; Neurites; Neuronal Injury; Neurons; Neuropeptides; Organ; Paracrine Communication; Peripheral; Peripheral Nervous System; Phenotype; Play; Property; Proteins; Recovery; Recovery of Function; Research Support; Role; Sensory; Signal Transduction; Source; Specificity; Spinal Cord; Stimulus; Stroke; Sympathetic Ganglia; System; Testing; Therapeutic Agents; Tissues; Trauma; Viral; Withdrawal; Work; autocrine; axon regeneration; central nervous system injury; chemotherapeutic agent; cognitive function; conditioning; cytokine; improved; in vitro Assay; in vivo; in vivo regeneration; injured; interest; leukemia inhibitory factor; nerve injury; neurotrophic factor; normal aging; overexpression; pituitary adenylate cyclase activating polypeptide; public health relevance; receptor; relating to nervous system; research study; response; transcriptional coactivator p75; uptake

DESCRIPTION (provided by applicant): Neural damage can arise from trauma, disease states, a side effect of certain therapeutic agents, or normal aging and can result in impaired motor, sensory, autonomic, and/or cognitive functions. A major problem in recovery from CNS damage is the general failure of axons to regenerate after injury. In contrast, peripheral neurons respond to nerve injury by axonal regeneration. This difference has been attributed to the environment through which the injured neurons must grow and the neurons' "intrinsic growth properties". The latter is believed to reside in the ability of axotomized peripheral neurons to make adaptive changes in gene expression. These changes may underlie the observation that regeneration of peripheral neurons is enhanced by a conditioning lesion. We are interested in the signals that trigger the conditioning lesion effect. During the previous grant period, we made the intriguing observation that treatment of animals with an antiserum to NGF produces a conditioning lesion-like effect in sympathetic neurons in culture. This finding has led us to hypothesize that "a reduction in the availability of target-derived trophic factors after injury is a stimulus for regeneration". We propose to test this hypothesis further by (a) examining the specificity of this effect using highly specific antibodies to NGF and the related neurotrophin NT-3, (b) blocking NGF's action by injecting antibodies directly into a sympathetic target tissue, (c) blocking NGF's actions by a second approach, i.e., administration of receptor bodies, (d) determining whether the antibody treatment promotes regeneration in vivo, and (e) determining the impact of overexpressing NGF in sympathetic ganglia using a viral construct. We have further hypothesized that anti-NGF produces its effects on the intrinsic growth properties of sympathetic neurons by down-regulating BDNF- and p75-mediated inhibition of neurite outgrowth, and we will test this hypothesis by (a) determining the impact of antibodies to NGF on BDNF levels in sympathetic neurons, (b) determining whether antibodies to BDNF by themselves trigger a conditioning lesion-like effect, and (c) seeing if the conditioning lesion effect is absent or reduced in p75 -/- mice. Work from other laboratories has established that elevation of cAMP plays a critical role in mediating the conditioning lesion effect. One of the genes that is elevated after nerve injury in sensory, motor, and sympathetic neurons is pituitary adenylate cyclase activating polypeptide (PACAP). PACAP stimulates cAMP synthesis and its own expression is elevated by cAMP. We propose to test the hypothesis that PACAP is involved in the conditioning lesion effect either upstream or downstream of cAMP or both using PACAP -/- mice. The proposed experiments will significantly further our understanding of the role of neurotrophins and neuropeptides in promoting nerve regeneration and how these agents might be used to enhance clinical recovery both in the peripheral nervous system and, hopefully, in the CNS. PUBLIC HEALTH RELEVANCE following nerve damage, nerve cells in the peripheral nervous system are able to regenerate, while nerve cells in the central nervous system (i.e., the brain and spinal cord) are not. This proposal focuses on identifying molecules that trigger regeneration with the idea that they might be used to enhance regeneration in the periphery and promote regeneration in the central nervous system.

描述（由申请人提供）：神经损害可能来自创伤，疾病状态，某些治疗剂的副作用或正常衰老，并可能导致运动，感觉，自主神经和/或认知功能受损。从中枢神经系统损伤中恢复的一个主要问题是轴突在受伤后的总体失败。相反，周围神经元通过轴突再生应对神经损伤。这种差异归因于受伤神经元必须生长和神经元的“内在生长特性”的环境。据信后者驻留在轴轴化周围神经元对基因表达的适应性变化的能力中。这些变化可能是一个观察到的观察，即调节病变可以增强周围神经元的再生。我们对触发调节病变效果的信号感兴趣。在上一个赠款期间，我们引人入胜的观察，即对NGF的抗血清的动物进行治疗 在培养物中的交感神经元中产生调节性病变样作用。这一发现使我们进入了 假设“受伤后目标衍生的营养因素的可用性减少是再生的刺激”。我们建议通过（a）使用对NGF和相关神经营养蛋白NT-3的高度特异性抗体检查这种效果的特异性，以进一步检验该假设。体内和（e）使用病毒构建体确定过表达NGF在交感神经节中的影响。我们进一步指出，抗NGF通过下调BDNF和p75介导的神经突生长的抑制，对交感神经元的固有生长特性产生影响，我们将通过（a）确定抗体对抗体的影响（a）确定抗体的影响（a）（a）（a）是否对同情NGF的影响（a）（a）（a）（a）（a）（a）（a）（a）（a）（a）（a）（A）触发条件病变样效应，（c）查看p75 - / - 小鼠中是否没有调节病变效应。来自其他实验室的工作已经确定，营地的升高在介导调节病变效应中起着至关重要的作用。在感觉，运动和交感神经元中神经损伤后升高的基因之一是垂体腺苷酸环化酶激活多肽（PACAP）。 PACAP刺激营地的合成，其自身的表达被营地提升。我们建议检验以下假设：PACAP参与cAMP上游或下游或使用PACAP - / - 小鼠的调节病变效应。提出的实验将 重要的是，我们对神经营养蛋白和神经肽在促进神经再生中的作用以及如何使用这些药物来增强周围神经系统中的临床恢复以及希望在CNS中的临床恢复。 神经损伤后的公共卫生相关性，周围神经系统中的神经细胞能够再生，而中枢神经系统中的神经细胞（即大脑和脊髓）却没有。该提案着重于识别触发再生的分子，以此来增强它们的再生。 外围和促进中枢神经系统的再生。