Crosstalk between NGS Receptors, TrkA & P75

NGS 受体之间的串扰，TrkA

• 批准号: 7418936
• 负责人: SUNG OK YOON
• 金额: $ 32.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418936
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Antibodies; Apoptosis; Apoptotic; Axotomy; Behavior; Binding; Biochemical; CNTNAP1 gene; Cell Death; Cell Survival; Cell physiology; Cells; Ceramides; Cessation of life; Cleaved cell; Collaborations; Complement component C1s; Complex; Condition; Cyclins; Data; Development; Disease; Disruption; Down-Regulation; Equilibrium; ErbB4 gene; Family; Funding; Glucose; Goals; Grant; Guanidines; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hand; Histidine; In Vitro; Injury; Intercept; Kinetics; Knockout Mice; Knowledge; Lesion; Ligands; Limb Tremors; Link; MAPK10 gene; MAPK8 gene; Maintenance; Manuscripts; Mediating; Modeling; Mus; Myelin; Natural regeneration; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nervous system structure; Neuregulin Receptor; Neuregulins; Neurites; Neuronal Injury; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; New York; Numbers; Oligodendroglia; Outcome; Outcome Study; PC12 Cells; Pathway interactions; Phenotype; Physiological; Play; Point Mutation; Preparation; Principal Investigator; Production; Progress Reports; Protein Isoforms; Publications; Published Comment; Publishing; Purpose; Rattus; Receptor Signaling; Recombinants; Recruitment Activity; Regulation; Relative (related person); Reporting; Research; Research Personnel; Resistance; Role; Schwann Cells; Seizures; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Source; Sphingolipids; Sphingosine; Spinal Cord; Spinal cord injury; Staging; Staining method; Stains; Synaptic Transmission; System; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Wallerian Degeneration; Work; attenuation; axon growth; base; blocking factor; caspase-3; caveolin 1; central nervous system injury; guanidinium; in vivo; injured; killings; man; mutant; neurotrophic factor; prevent; progenitor; programs; promoter; receptor; response; rho; rho GTPase-activating protein; rhoB p20 GDI; sortilin; sphingosine 1-phosphate; stem; transcriptional coactivator p75

DESCRIPTION (provided by applicant): Neurotrophins play key regulatory roles in cellular processes that are required for proper development and maintenance of the nervous system, such as cell survival/death, axon growth/guidance, and synaptic transmission/plasticity. Both Trk receptors and p75 participate in mediating these diverse neurotrophin actions, but p75 is mainly responsible for neurotrophin-dependent cell death at specific stages during development or under pathological conditions in the adult. The overall goal of this project is to understand the signaling mechanisms that underlie NGF's action regarding cell death and survival, with a focus on Rac and Rho, which are regulated by p75. P75 activates Rac in a prolonged manner that correlates with apoptosis, while co-activation of Trk/p75 leads to transient Rac activation and cell survival. These results suggest that the kinetics of Rac activation may be the key determinant in cellular outcome between cell survival and death. Regulation of Rho, on the other hand, may be determined by which coreceptor that p75 associates with: With neurotrophins/Trk, p75 inhibits Rho, while it activates Rho as a co-receptor for the Nogo receptor, NgR. P75 is often induced by injury in the adult nervous system and its expression in such cases has been linked to apoptosis. After the experimental injuries that induced p75 and cell death, Rho was activated, suggesting that controlling Rho activation by p75 will be critical in preventing cell death and degeneration after injuries. Our overall hypothesis is therefore that regulation of Rac and Rho by p75 determines the outcome between cell death and survival/regeneration. In an effort to understand the mechanisms by which p75 activates Rac and Rho, we discovered that the Kalirin family of guanidine exchange factors (GEF), Kalirin7 and 9, bind p75. Kalirin7 contains a Rac GEF domain, while Kalirin9 contains both Rac and Rho GEF domains. The specific aims include: (1) To determine the mechanisms of transient Rac activation by Kalirin7, (2) To determine whether prolonged Rac activation is necessary for apoptosis, and (3) To determine whether Kalirin9 is responsible for regulating the opposite's action of p75 for Rho activity both in vitro and in vivo after spinal cord injury. The outcome of this study will result in significant advancement of the current knowledge of NGF signaling, by elucidating the basic biochemical mechanisms behind the complex interplay between p75 and Trk, as well as p75 and NgR. A detailed understanding of the mechanisms may ultimately prompt therapeutic strategies for promoting regeneration and limiting degeneration in cases of neuronal injury and disease.

描述（由申请人提供）：神经营养因子在神经系统正常发育和维持所需的细胞过程中发挥关键的调节作用，例如细胞存活/死亡，轴突生长/引导和突触传递/可塑性。Trk受体和p75都参与介导这些不同的神经营养因子作用，但p75主要负责在发育的特定阶段或成人病理条件下神经营养因子依赖性细胞的死亡。该项目的总体目标是了解NGF在细胞死亡和存活方面的作用的信号机制，重点关注由p75调节的Rac和Rho。P75激活Rac的时间较长，与细胞凋亡有关，而Trk/ P75的共激活导致Rac的短暂激活和细胞存活。这些结果表明，Rac活化动力学可能是细胞存活和死亡之间细胞结局的关键决定因素。另一方面，Rho的调节可能取决于p75与哪个辅助受体相关：与神经营养因子/Trk一起，p75抑制Rho，而它激活Rho作为Nogo受体NgR的辅助受体。P75通常由成人神经系统损伤引起，在这种情况下，P75的表达与细胞凋亡有关。在诱导p75和细胞死亡的实验损伤后，Rho被激活，这表明通过p75控制Rho的激活对于防止损伤后细胞死亡和变性至关重要。因此，我们的总体假设是p75对Rac和Rho的调控决定了细胞死亡和存活/再生之间的结果。为了了解p75激活Rac和Rho的机制，我们发现Kalirin家族的胍交换因子（GEF） Kalirin7和kalirin9与p75结合。Kalirin7包含Rac GEF域，而Kalirin9同时包含Rac和Rho GEF域。具体目的包括：(1)确定Kalirin7短暂激活Rac的机制；(2)确定细胞凋亡是否需要持续的Rac激活；(3)确定Kalirin9是否负责调节p75在脊髓损伤后体外和体内对Rho活性的相反作用。本研究的结果将通过阐明p75和Trk以及p75和NgR之间复杂相互作用背后的基本生化机制，从而显著提高当前对NGF信号传导的认识。对其机制的详细了解可能最终促使在神经元损伤和疾病的情况下促进再生和限制变性的治疗策略。