Proteoglycan Signaling as a New Therapeutic Target for Cocaine Addiction

描述（由申请人提供）：这项修订后的拨款提案的目标是探索调节脑蛋白多糖syndecan-3的活性以治疗可卡因滥用的策略。像syndecan-3这样的蛋白聚糖，虽然最初被确定为细胞外基质（ECM）的成分，但也作为生长因子和ECM蛋白的受体和共受体发挥信号功能。我们观察到外侧下丘脑（LH）的syndecan-3在限制强迫性可卡因摄入方面具有意想不到的新作用。特别地，在Specific Aim 1中，我们将研究syndecan-3外结构域脱落和信号转导在可卡因摄入调节中的作用。syndecan-3外结构域的蛋白水解裂解，也称为“脱落”，是在配体相互作用后诱导的，并终止其信号传导。为了探索外结构域脱落的功能后果，我们将使用腺相关（AAV）病毒载体递送修饰的syndecan-3构建物，包括抗脱落syndecan-3、syndecan-3外结构域和未修饰的syndecan-3。这些研究的结果将确立抑制其配体结合外畴的蛋白水解裂解的治疗潜力。特异性目的2的研究将探讨syndecan-3作为替代GDNF受体在syndecan-3减少可卡因自我给药能力中的作用。为此，我们将使用AAV转导修饰的GDNF结构，旨在选择性地结合syndecan-3或其典型的高亲和力受体GFR-¿1。Specific Aim 2的结果将为未来的研究提供信息，旨在操纵syndecan-3与其两个受体系统和信号转导伙伴之间的相互作用，以增强其信号传导活性。总之，拟议的研究将增加我们对下丘脑蛋白多糖syndecan-3作为行为调节剂的功能的理解，并将探索治疗可卡因滥用的创新治疗策略。

DESCRIPTION (provided by applicant): 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-bindig 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.