Role of Fibroblasts in Axon Regeneration after SCI

描述（由申请人提供）：脊髓损伤（SCI）导致瘢痕组织的形成，瘢痕组织是轴突再生的有效屏障。这种疤痕是由啮齿动物和人类的细胞外基质（ECM）分子过度沉积组成的。为什么大多数轴突不能生长到这个ECM丰富的区域还没有完全理解。体外试验表明成纤维细胞 作为抑制性ECM分子的主要来源，但这是否在体内也是如此尚不清楚。虽然脑膜被认为是SCI后成纤维细胞的主要来源，但最近的证据表明血管周围的小生境可能是瘢痕组织的替代来源。本提案的总体目标是确定血管周围成纤维细胞在瘢痕形成中的作用，以通过追求以下目标促进挫伤性SCI后的轴突再生：1）确定挫伤性SCI后成纤维细胞的时空分布和细胞命运2）确定成纤维细胞消融对SCI后瘢痕形成和轴突再生的影响。3)确定成纤维细胞PDGFR-<$在SCI后瘢痕形成和轴突再生中的作用。我们提出的研究将填补有关成纤维细胞在SCI动物模型中作用的知识空白，并可能揭示治疗SCI患者的新治疗靶点。 公共卫生相关性：脊髓损伤（SCI）患者患有永久性残疾，但治疗和治疗选择有限。永久性缺陷的一个主要原因是脊髓中的轴突无法通过损伤部位形成的瘢痕组织再生。成纤维细胞被认为是这种瘢痕组织的主要成分，但直接解决这个问题的动物研究有限。我们将在动物模型中使用遗传学和药理学来测试靶向成纤维细胞是否可以减少SCI后的瘢痕形成并促进轴突再生和功能恢复。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in formation of scar tissue that is a potent barrier to axon regeneration. This scar is comprised of excess deposition of extracellular matrix (ECM) molecules in both rodents and humans. Why most axons fail to grow into this ECM-rich region is not fully understood. In vitro assays have implicated fibroblasts as a major source of inhibitory ECM molecules, but whether this also true in vivo is not clear. While the meninges were thought to be the primary source of fibroblasts after SCI, recent evidence indicates that the perivascular niche could be an alternative source of the scar tissue. The overall goal of this proposal is to determine the role of perivascular fibroblasts in scar formation in order to promote axon regeneration after contusive SCI by pursuing the following aims: 1) Determine the temporospatial distribution and the cellular fate of fibroblasts after contusive SCI 2) Determine the effect of fibroblast ablation on scar formation and axon regeneration after SCI. 3) Determine the role of fibroblast PDGFR-¿ on scar formation and axon regeneration after SCI. Our proposed studies will fill a gap in knowledge about the role of fibroblasts in animal models of SCI and may reveal new therapeutic targets to treat SCI patients. PUBLIC HEALTH RELEVANCE: Patients with spinal cord injury (SCI) suffer from permanent disabilities but have limited treatment and therapeutic options. A major reason for the permanent deficits is the inability of axons in the spinal cord to regenerate through the scar tissue that develops at the injury site. Fibroblasts have been implicated as a major component of this scar tissue, but there have been limited animal studies directly addressing this issue. We will use genetics and pharmacology in animal models to test whether targeting fibroblasts can reduce scarring and promote axon regeneration and functional recovery after SCI.