Lymphatic ERG signaling in scleroderma fibrosis

硬皮病纤维化中的淋巴 ERG 信号传导

基本信息

批准号：
10661649
负责人：
MARIA TROJANOWSKA
金额：
$ 60.35万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-07 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661649
关键词：
Address Affect Animals Autoimmunity Automobile Driving Biopsy Bleomycin Blood Blood Cells Blood Vessels CCL21 gene Cause of Death Cell Proliferation Cell physiology Cell secretion Cells Data Defect Dendritic Cells Dermal Development Disease Endothelial Cells Endothelium FLT4 gene Family Feedback Fibrosis Functional Regeneration Gene Expression Profiling Genes Genetic Transcription Goals Homeostasis Immune Impaired wound healing Impairment In Vitro Inflammatory Injury Intercellular Junctions Knock-out Knowledge Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Lymphocyte Molecular Molecular Target Mus NOTCH1 gene NOTCH4 gene Natural regeneration Organ Pathologic Pathologic Neovascularization Pathway interactions Patients Phenotype Physiologic Neovascularization Physiological Physiological Processes Platelet Activation Predisposition Proliferating Publishing Pulmonary Fibrosis Role SOX18 gene Sampling Scleroderma Serum Signal Pathway Signal Transduction Signaling Molecule Skin Specific qualifier value Systemic Scleroderma Testing Therapeutic Intervention Toxic Environmental Substances Translations Tube VEGFC gene Variant Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Vascular System angiogenesis body system experimental study improved in vivo lymphatic circulation lymphatic dysfunction lymphatic vasculature lymphatic vessel matrigel member mouse model novel postnatal prevent programs receptor repaired response response to injury skin fibrosis targeted treatment therapeutic target transcription factor vascular inflammation vascular injury wound healing

项目摘要

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.

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。