Lymphatic ERG signaling in scleroderma fibrosis

SSc 的特点是自身免疫、小血管病变和纤维化，导致血管损伤 多器官系统。目前的证据表明，SSc 源于内皮损伤，如果血管 新生血管生成反应无法修复损伤，下游病理性纤维化随之而来。类似于 血管系统方面，SSc 患者也有淋巴管稀疏的记录。相比之下 对于血液内皮细胞来说，控制淋巴系统缺陷的分子机制在很大程度上仍然存在 未经探索。我们的首要目标是描绘导致损伤的分子和细胞机制 SSc 中的血液和淋巴系统。为了改善 SSc 血管疾病的治疗选择，有一个 迫切需要发现新的分子靶点。选择性调节缺乏的信号分子 血液和淋巴内皮细胞都是治疗干预的理想目标。此外， 尽管越来越多的证据表明淋巴循环受损，但尚无研究表明 解决了 SSc 中淋巴系统受损的机制。根据已发表的 和我们新的初步数据，我们假设转录因子 ERG 是细胞再生所必需的 淋巴管系统及其缺陷会导致伤口愈合受损和纤维化。此外，我们 假设 ERG 缺陷是血液之间共同的病理特征，但存在重大差异 SSc 患者的淋巴内皮细胞，这可能导致血管生成受损和 这些患者的淋巴管生成。我们建议使用综合策略，包括基因分析 在从 SSc 和对照皮肤活检中新鲜分离的 BEC 和 LEC 中表达，以及我们新的 基于出生后血液和淋巴管中 Erg 的缺失，开发了 SSc 血管病变小鼠模型 细胞和机制体外研究，以从分子和功能上表征 ERG 缺陷在 血液和淋巴系统。我们提出以下三个目标： 在目标 1 中，我们将研究角色和 LEC 中 ERG 缺陷的功能意义，重点关注控制增殖的信号通路；在 目标 2 我们将使用谱系追踪来确定 Erg 内皮缺陷在 生理性新血管生成和新淋巴管生成；在目标 3 中，我们将确定 Erg 淋巴管是否 缺乏会导致纤维化的易感性增加。如果成功，拟议的研究有可能 建立与淋巴细胞功能相关的新基础知识并剖析驱动 SSc 的新机制 淋巴管病。

SSc is characterized by autoimmunity, small blood vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Current evidence posits that SSc originates from the endothelial injury, and if vascular neoangiogenic response fails to repair the damage, downstream pathological fibrosis ensues. Analogous to the blood vascular system, rarefaction of lymphatic vessels has also been documented in SSc patients. In contrast to the blood endothelium, the molecular mechanisms governing the lymphatic system defects remain largely unexplored. Our overarching goal is to delineate the molecular and cellular mechanisms that drive impairment of blood and lymphatic systems in SSc. To improve treatment options for SSc vascular disease, there is an urgent need in uncovering new molecular targets. The signaling molecules that selectively regulate deficiency of both blood and lymphatic endothelial cells would be desirable targets for therapeutic intervention. Furthermore, although there is increased evidence of impaired lymphatic circulation, there have been no studies that addressed the mechanisms responsible for the impairment of the lymphatic system in SSc. Based on published and our new preliminary data, we hypothesize that transcription factors ERG is required for regeneration of lymphatic vasculature and its deficiency leads to impaired wound healing and fibrosis. Furthermore, we hypothesize that deficiency of ERG is a shared pathological feature, yet with critical variations, between blood and lymphatic endothelial cells in SSc patients, which may contribute to impaired angiogenesis and lymphangiogenesis in these patients. We propose to use a comprehensive strategy, including analysis of gene expression in freshly isolated BEC and LEC from SSc and control skin biopsies, together with our newly developed mouse models of SSc vasculopathy based on the postnatal deletion of Erg in blood and lymphatic cells, and mechanistic in vitro studies to molecularly and functionally characterize the role of ERG deficiency in blood and lymphatic systems. We propose the following three aims: In Aim 1 we will investigate the role and functional significance of ERG deficiency in LEC focusing on the signaling pathways controlling proliferation; In Aim 2 we will use lineage tracing to determine the functional consequences of Erg endothelial deficiency during physiological neo-angiogenesis and neo-lymphangiogenesis; In Aim 3 we will determine if Erg lymphatic deficiency leads to increased susceptibility to fibrosis. If successful, the proposed study has the potential to establish new basic knowledge pertinent to lymphatic cell function and dissect novel mechanism(s) driving SSc lymphangiopathy.