Proteoglycan Signaling as a New Therapeutic Target for Cocaine Addiction

摘要 这项修订后的拨款提案的目标是探索调节大脑活动的策略。 蛋白多糖Syndecan-3用于治疗可卡因滥用。蛋白多糖喜欢Syndecan-3，而 最初被确定为细胞外基质(ECM)的组成部分，也发挥信号功能，如 生长因子和细胞外基质蛋白的受体和辅助受体。我们观察到Syndecan-3在 下丘脑外侧核在限制强迫性可卡因摄入方面有一个意想不到的新作用。 特别是，在特定目标1中，我们将研究syndecan-3胞外结构域的脱落和信号 可卡因摄入量调节中的转导作用。Syndecan-3胞外结构域的蛋白水解性切割 所谓的“脱落”是在配体相互作用后诱导并终止其信号转导的。去探查 胞外区脱落的功能后果，我们将使用腺相关(AAV)病毒载体 提供改良的Syndecan-3结构，包括防脱落的Syndecan-3，Syndecan-3 单独的胞外结构域，以及未经修饰的Syndecan-3。这些研究的结果将确立 抑制其配体结合胞外结构域蛋白水解性切割的治疗潜力。研究项目： 特异性目标2将研究Syndecan-3作为一种替代的GDNF受体在 Syndecan-3可减少可卡因的自我给药。为此，我们将使用AAV来转换修改的 旨在选择性结合Syndecan-3或其典型的高亲和力的GDNF构建物 受体GFR-？1。特异性目标2的结果将为未来旨在操纵 Syndecan-3与其两个受体系统及信号转导伙伴的相互作用促进 它的信号活动。 总之，拟议的研究将增加我们对下丘脑功能的了解 蛋白多糖Syndecan-3作为行为调节剂，将探索创新的治疗策略 可卡因滥用的治疗。

Summary The goal of this revised grant proposal is to explore strategies to modulate the activity of the brain proteoglycan syndecan-3 for the therapy of cocaine abuse. Proteoglycans like syndecan-3, while originally identified as components of the extracellular matrix (ECM), also play signaling functions as receptors and co-receptors for growth factors and ECM proteins. We observed that syndecan-3 in the lateral hypothalamus (LH) has an unexpected new role in limiting compulsive cocaine intake. In particular, in Specific Aim 1 we will investigate syndecan-3 ectodomain shedding and signal transduction in the regulation of cocaine intake. The proteolytic cleavage of syndecan-3 ectodomain, also known as "shedding" is induced after ligand interaction and terminates its signaling. To probe the functional consequence of ectodomain shedding, we will use adeno-associated (AAV) viral vectors to deliver modified syndecan-3 constructs including a shedding-resistant syndecan-3, the syndecan-3 ectodomain alone, and the unmodified syndecan-3. The results of these studies will establish the therapeutic potential of inhibiting the proteolytic cleavage of its ligand-binding ectodomain. Studies in Specific Aim 2 will investigate the role of syndecan-3 as an alternative GDNF receptor in the ability of syndecan-3 to reduce cocaine self-administration. To this end we will use AAV to transduce modified GDNF constructs designed to bind selectively either to syndecan-3 or to its canonical high-affinity receptor GFR-¿1. The results of Specific Aim 2 will inform future studies aimed at manipulating interactions between syndecan-3 and its two receptor systems and signal transduction partners to boost its signaling activity. Together, the proposed studies will increase our understanding of the functions of the hypothalamic proteoglycan syndecan-3 as a regulator of behavior and will explore innovative therapeutic strategies for the therapy of cocaine abuse.