p75NTR Ligands for Treament of Traumatic Brain Injury

用于治疗创伤性脑损伤的 p75NTR 配体

• 批准号: 8394596
• 负责人: STEPHEN M. MASSA
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394596
• 关键词: Acute; Address; Adult; Animals; Apoptotic; Behavior; Behavioral; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cause of Death; Cell Death; Cell Death Inhibition; Cell Death Process; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chronic; Chronic Phase; Clinical; Corticospinal Tracts; Craniocerebral Trauma; Development; Drug Kinetics; Early treatment; Effectiveness; Exhibits; Explosion; Focal Brain Injuries; General Population; Goals; Growth; Hippocampus (Brain); Hour; In Vitro; Injury; Knowledge; Lead; Life; Ligands; MAGED1 gene; MAPK8 gene; Mediating; Memory; Modeling; Mus; Myelin; NGFR Protein; Natural regeneration; Nature; Nerve Cell Survival; Nerve Degeneration; Nerve Growth Factor Receptors; Neurites; Neurologic; Neurons; Oligodendroglia; Outcome; PI3K/AKT; Pain; Pathologic; Pathway interactions; Penetration; Pharmaceutical Preparations; Population; Process; Property; Proto-Oncogene Proteins c-akt; Recovery; Rehabilitation therapy; Research; Role; Signal Pathway; Signal Transduction; Spinal Cord; Stem cells; Structure; Swimming; Symptoms; Testing; Time; Tissues; Toxic effect; Training; Trauma; Traumatic Brain Injury; Traumatic CNS injury; Veterans; Work; axon regeneration; base; central nervous system injury; cholinergic; combat; controlled cortical impact; density; depressive symptoms; disability; drug development; effective therapy; falls; gliogenesis; improved; injured; insight; knockout animal; mind control; morris water maze; motor function improvement; nerve stem cell; neurogenesis; neuronal cell body; neuronal survival; neurotrophic factor; polypeptide; pressure; public health relevance; receptor; receptor coupling; receptor function; repaired; research study; response; small molecule; vehicular accident

DESCRIPTION (provided by applicant): Project Summary: Traumatic brain injuries (TBIs) constitute a significant and growing percentage of injuries in the veteran population; sequelae of explosions, motor vehicle accidents and falls. TBI is also a major cause of death and disability in the general population of the US, particularly in those under 40. Approximately 2% of the population is living with a chronic TBI-related disability. There are currently no effective protective or restorative therapies available clinically. In several models of CNS trauma, administration of a neurotrophin (e.g. BDNF, NGF) protects tissues acutely and promotes longer term recovery. However, the neurotrophins are poor drugs as they are labile, exhibit poor CNS penetration and may augment cell death and pain pathways. These properties are due to their polypeptide composition and the stimulation of intersecting signalling pathways through the activation of multiple receptors. These problems may be at least partially circumvented through the use of recently discovered small, stable, non-peptidyl drug-like compounds (designated LM11A) that potently promote neuronal survival through selective interactions with the neurotrophin receptor p75NTR, inhibit proNGF-induced death, and promote neural progenitor cell proliferation. p75NTR and proNGF have been implicated in several neurodegenerative processes, including the apoptotic death of oligodendrocytes in the spinal cord and corticospinal tract neurons in the brain following trauma. We hypothesize that the LM11A compounds will inhibit cell death occurring hours to days following a traumatic injury, and further, that effects on neurogenesis and neurite plasticity will improve brain structure and function at times remote (weeks, months) from the injury. In addition, we postulate that these effects will occur in association with the promotion of survival and differentiative signaling (e.g. via AKT, ERK, NF:B pathways) by the compound, and the suppression of death signaling (e.g. via JNK activation). The specific aims of this proposal are to: 1) to examine changes in cell signaling associated with the inhibition of cell death by a p75NTR-directed compound (LM11A-31) in the context of focal brain trauma, 2) to determine the responses of a model of focal brain trauma to LM11A-31 given in an early/delayed fashion, and in the late/chronic phase, and 3) to determine the roles of p75NTR following injury. Towards these aims, a controlled cortical impact (CCI) model of brain trauma in mice will be used to assess the effects of the LM11A-31 on cell survival and signalling, neuro- and gliogenesis, cholinergic neurite density, and 'depressive' (Porsolt Forced Swim Test) and memory (Morris Water Maze) behaviors in animals treated immediately, up to 24 hrs, or beginning 2 weeks following injury. To further examine p75NTR function and compound mechanisms in TBI, cell death, process dystrophy and neurogenesis will be evaluated in p75NTR deficient animals subjected to CCI. These studies will provide information important for the eventual application of these or related compounds to clinical head trauma, and will advance our knowledge of the roles of p75NTR in pathologic states. The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions.

描述（由申请人提供）：