Crosstalk between NGS Receptors, TrkA & P75

NGS 受体之间的串扰，TrkA

• 批准号: 7015045
• 负责人: SUNG OK YOON
• 金额: $ 33.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015045
• 关键词: apoptosis; biological signal transduction; cell growth regulation; gene expression; genetically modified animals; growth factor receptors; guanine nucleotide binding protein; guanine nucleotide exchange factors; laboratory mouse; laboratory rat; nerve growth factors; neurogenesis; protein protein interaction; spinal cord injury

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调节作用，如细胞存活/死亡、轴突生长/指导和突触传递/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主要负责在发育期间或在成人病理条件下的特定阶段的神经营养因子依赖性细胞死亡。该项目的总体目标是了解神经生长因子对细胞死亡和存活的作用的信号机制，重点是由p75调节的Rac和Rho。P75以与细胞凋亡相关的延长的方式激活Rac，而Trk/p75的共激活导致短暂的Rac激活和细胞存活。这些结果表明，Rac激活的动力学可能是细胞存活和死亡之间的细胞结果的关键决定因素。另一方面，Rho的调节可以通过p75与哪种辅助受体结合来确定：对于神经营养因子/Trk，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中的损伤诱导，并且在这种情况下其表达与细胞凋亡有关。在诱导p75和细胞死亡的实验性损伤后，Rho被激活，这表明通过p75控制Rho激活对于防止损伤后的细胞死亡和变性至关重要。因此，我们的总体假设是，通过p75调节Rac和Rho决定了细胞死亡和存活/再生之间的结果。为了理解p75激活Rac和Rho的机制，我们发现胍交换因子（GEF）的Kalirin家族，Kalirin 7和9，结合p75。Kalirin 7包含Rac GEF域，而Kalirin 9包含Rac和Rho GEF域。具体目标包括：（1）确定Kalirin 7瞬时激活Rac的机制，（2）确定延长的Rac激活是否是细胞凋亡所必需的，和（3）确定Kalirin 9是否负责调节p75对体外和体内脊髓损伤后Rho活性的相对作用。这项研究的结果将导致显着的进步，目前的知识，神经生长因子信号，通过阐明背后的复杂的相互作用p75和Trk，以及p75和NgR的基本生化机制。对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。