Nervous system regeneration, molecular basis in echinoderms

描述（由申请人提供）：缺乏有效的修复机制，包括有缺陷的纤维生长或有限的神经发生，是许多神经系统疾病或功能障碍的基础。因此，改善神经系统中的愈合和/或再生过程的能力具有深远的治疗效果以及经济效果。我们率先使用一种新的模型系统来研究神经系统再生，棘皮动物海参。该物种可以再生其桡神经索和肠神经系统的过程中，包括神经纤维的再生长和神经发生。棘皮动物与脊椎动物密切相关，因此，对该系统的细胞和分子过程的研究可以有助于阐明人类神经系统再生过程中所涉及的机制。在本提案中，我们专注于参与神经再生事件的几种蛋白质。其中包括：（1）Orpin，一种从海参中发现的新蛋白质;（2）黑素转铁蛋白，一种在许多脊索动物中发现的蛋白质，但其功能仍然难以捉摸;（3）两种众所周知的信号通路，Wnt和视黄酸，已被证明与其他物种的神经系统发育有关。对这些分子的研究将涉及神经系统再生的各个步骤，包括神经细胞分化和增殖，细胞凋亡和器官再生的神经依赖性。我们提出的实验，包括在体内和体外操作，以确定蛋白质和mRNA的时空表达模式，以及蛋白质的功能。预期的结果将有助于理解海参神经系统惊人再生的分子机制，并将为人类如何实现这种再生提供重要线索。

DESCRIPTION (provided by applicant): The lack of an efficient repair mechanism that includes defective fiber growth or limited neurogenesis is the basis for many diseases or malfunctions of the nervous system. Consequently, the capacity to improve healing and/or regeneration processes in the nervous system has profound therapeutic, as well as economical consequences. We have pioneered the use of a novel model system to study nervous system regeneration, The echinoderm Holothuria glaberrima. This species can regenerate both its radial nerve cord and enteric nervous system in a process that includes re-growth of nerve fibers and neurogenesis. Echinoderms are closely related to vertebrates, thus, the study of cellular and molecular processes in this system can serve to illuminate the mechanisms involved in nervous system regenerative processes in humans. In the present proposal we focus on several proteins that are involved in nervous regenerative events. These include: (1) Orpin, a novel protein characterized from the holothurian, (2) melanotransferrin, a protein found in many chordates but whose function remains elusive, and (3) two well-known signaling pathways, Wnt and retinoic acid, that have been shown to be associated with nervous system development in other species. The study of these molecules will address various steps in the regeneration of the nervous system, including nerve cell differentiation and proliferation, apoptosis and nerve-dependency of organ regeneration. We propose experiments that include in vivo and in vitro manipulations to determine the protein and mRNA temporal and spatial expression patterns, as well as the protein function. The expected results will help understand the molecular mechanisms that underlie the amazing regeneration of the nervous system in holothurians and will provide important cues on how this regeneration might be achieved in humans.