Lymphatic ERG signaling in scleroderma fibrosis

SSc的特征是自身免疫、小血管病变和纤维化导致的损害。 多个器官系统。目前的证据表明，SSc起源于血管内皮损伤，如果血管 新生血管反应不能修复损伤，继而发生下游病理性纤维化。类似于 血管系统、淋巴管稀疏也被记录在SSc患者中。相比之下， 对于血液内皮细胞，淋巴系统缺陷的分子机制仍然很大程度上仍然存在。 未被开发的。我们的首要目标是描述驱动损伤的分子和细胞机制。 在SSC的血液和淋巴系统。为了改善SSc血管疾病的治疗选择，有一种 迫切需要发现新的分子靶标。选择性调节血管紧张素转换酶缺乏的信号分子 血液和淋巴管内皮细胞都是治疗干预的理想靶点。此外， 尽管有越来越多的证据表明淋巴循环受损，但还没有研究表明 阐述了SSc淋巴系统受损的机制。基于已发布的 和我们新的初步数据，我们假设转录因子ERG是再生所需的 淋巴管及其缺陷会导致伤口愈合和纤维化受损。此外，我们 假设ERG缺乏是一个共同的病理特征，但在血液中存在关键差异 和淋巴管内皮细胞，这可能有助于血管生成受损和 这些患者的淋巴管生成。我们建议使用包括基因分析在内的综合策略 SSC和对照皮肤活检组织中新分离的BEC和LEC中的表达 基于出生后血液和淋巴中ERG缺失的SSc血管病变小鼠模型的建立 细胞和机制的体外研究，以分子和功能表征的作用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，我们将调查 ERG缺陷在LEC中的功能意义侧重于控制增殖的信号通路 目的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 缺乏会增加纤维化的易感性。如果成功，这项拟议的研究有可能 建立与淋巴细胞功能相关的新基础知识，剖析干细胞驱动新机制(S) 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.