Type I interferon regulates angiogenesis in Down Syndrome Supplement

I 型干扰素在唐氏综合症补充剂中调节血管生成

基本信息

批准号：
10834514
负责人：
Denise Al-Alam
金额：
$ 6.33万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
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：
2022-09-06 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10834514
关键词：
Adult Alveolus Angiogenesis Inhibitors Angiogenic Factor Arteries Automobile Driving Blood capillaries Cell Culture Techniques Cell Proliferation Cells Chromosome abnormality Data Defect Development Dilatation - action Down Syndrome Endothelial Cells Endothelium Exhibits Hemosiderosis Human Impairment In Situ Individual Interferon Type I Intervention Link Lung Lung diseases Lymphatic Muscle Nature Pathway interactions Permeability Play Population Proliferating Pulmonary Heart Disease Pulmonary Hypertension Reporting Role Signal Transduction Signaling Protein Stains Structure Syndrome System Testing Three-Dimensional Image Tube Vegf inhibition angiogenesis combinatorial endothelial stem cell improved in utero induced pluripotent stem cell lung development migration new therapeutic target peripheral blood prevent pulmonary hypoplasia pulmonary vascular disorder spatiotemporal transcriptome sequencing transcriptomics

项目摘要

SUMMARY: Trisomy 21 (T21) is the most prevalent chromosomal abnormality worldwide, resulting in Down Syndrome (DS) [1, 2], a multisystem syndrome associated with cardiopulmonary disorders. Pulmonary disorders include pulmonary hypertension, pulmonary hypoplasia, pulmonary hemosiderosis and pulmonary capillaritis, all of which can result from a dysregulated lung endothelium. In addition, T21 lungs are characterized by the persistence of an immature double capillary network system surrounding the alveoli and representative of the saccular stage of development [3]. This suggests that endothelial defects in individuals with DS are likely initiated in utero. Single cell transcriptomics data demonstrated the presence of diverse endothelial cell populations in the human adult lung [4, 5]. While others and we have reported impaired endothelial networks in the developing T21 lung characterized by congested capillaries, lymphatic dilatation, and muscularized arteries [6], the nature of these defects and the different endothelial cell populations contributing to such defects are yet to be understood. Moreover, developing T21 human lungs display increased expression of anti-angiogenic factors [3, 6-8]. A decrease in endothelial progenitor cells is found in T21 peripheral blood [9]. Furthermore, T21 iPSC- derived endothelial cells exhibit decreased cell proliferation, impaired sprouting and tube formation compared to euploid cells [10]. One of the major pathways consistently activated in DS is the type I interferon (IFN) pathway [6]. Elevated type I IFN causes a decrease of endothelial progenitor cells [9] and inhibits VEGF induced development of capillary like structures [11, 12], thus playing an anti-angiogenic role. Additionally, type I interferonopathies are linked to pulmonary hypertension and pulmonary vasculopathy [13]. Sc-RNAseq data of T21 and euploid lung cells demonstrated the presence of several endothelial cell populations displaying increased expression of type I IFN signaling pathway genes in T21. Therefore, we hypothesize that defective lung angiogenesis occurs in T21 during development and is a result of type I IFN-dependent changes in endothelial cell proliferation, differentiation and migration. To test this hypothesis, we will 1) determine endothelial cell defects in T21 vs euploid human developing lungs by defining the different endothelial cell populations and their spatiotemporal distribution using combinatorial in situ hyridization with IF stainings and assessing defects in endothelial cell proliferation and sprouting of each group via IF and 3D image quantifications and 2) define the role of type I IFN signaling in the endothelial defects in T21 by determining the effect of gain and loss of type I IFN signaling on proliferation, migration, permeability and tube formation in primary and iPSC-derived endothelial cell cultures of T21 and euploid cells. Improved strategies to prevent, ameliorate or reverse endothelial related lung disease in DS will be contingent upon a detailed understanding of the defects and pathways driving these defects that may identify novel therapeutic targets for intervention.

概括： 21 三体 (T21) 是全球最常见的染色体异常，导致唐氏综合症 (DS) [1, 2]，一种与心肺疾病相关的多系统综合征。肺部疾病包括肺动脉高压、肺发育不全、肺含铁血黄素沉着症和肺毛细血管炎等这可能是由于肺内皮失调引起的。此外，T21肺的特点是肺泡周围存在不成熟的双毛细血管网络系统，代表囊状发育阶段[3]。这表明 DS 患者的内皮缺陷可能是由在子宫内。单细胞转录组学数据证明了不同内皮细胞群的存在成人肺 [4, 5]。虽然其他人和我们都报告了发育中的内皮网络受损 T21肺的特点是毛细血管充血、淋巴管扩张和动脉肌化[6]，性质这些缺陷以及导致这些缺陷的不同内皮细胞群尚未确定明白了。此外，发育中的 T21 人肺显示抗血管生成因子表达增加 [3， 6-8]。 T21 外周血中发现内皮祖细胞减少 [9]。此外，T21 iPSC- 与相比，衍生的内皮细胞表现出细胞增殖减少、发芽和管形成受损整倍体细胞[10]。 DS 中持续激活的主要途径之一是 I 型干扰素 (IFN) 途径 [6]。 I 型 IFN 升高导致内皮祖细胞减少 [9] 并抑制 VEGF 诱导的毛细血管样结构的发育[11, 12]，从而发挥抗血管生成作用。另外，I型干扰素病与肺动脉高压和肺血管病有关[13]。 Sc-RNAseq 数据 T21 和整倍体肺细胞证明存在多个内皮细胞群 T21 中 I 型 IFN 信号通路基因的表达增加。因此，我们假设有缺陷肺血管生成发生在 T21 发育过程中，是 I 型 IFN 依赖性变化的结果内皮细胞增殖、分化和迁移。为了检验这个假设，我们将 1) 确定内皮细胞通过定义不同的内皮细胞群和 T21 与整倍体人类发育肺中的细胞缺陷使用组合原位杂交和 IF 染色来评估它们的时空分布并评估缺陷通过 IF 和 3D 图像定量分析各组的内皮细胞增殖和出芽情况，2) 定义通过确定 I 型干扰素获得和缺失的影响，研究 I 型干扰素信号传导在 T21 内皮缺陷中的作用 IFN 信号传导对原代和 iPSC 衍生内皮细胞的增殖、迁移、通透性和管形成的影响 T21 和整倍体细胞的细胞培养物。预防、改善或逆转内皮相关疾病的改进策略 DS 肺部疾病的治疗取决于对驱动这些疾病的缺陷和途径的详细了解可能确定新的干预治疗靶点的缺陷。