Defining the role of mechanoresponsive adipocyte-to-fibroblast transition in wound fibrosis.

定义机械反应性脂肪细胞向成纤维细胞转变在伤口纤维化中的作用。

基本信息

批准号：
10654464
负责人：
MICHAEL T LONGAKER
金额：
$ 34.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654464
关键词：
Adipocytes Adipose tissue Adopted Adult Anatomy Cells Cicatrix Clinical Communication Cutaneous Data Deposition Dermal Development Dipeptidyl-Peptidase IV Extracellular Matrix Fibroblasts Fibrosis Flow Cytometry Focal Adhesion Kinase 1 Genes Genetic Growth Histologic Histology Human Hypertrophic Cicatrix Immunohistochemistry In Situ In Vitro Injury Knockout Mice Machine Learning Mechanics Medical Modeling Molecular Morbidity - disease rate Mus Myofibroblast Natural regeneration Pathway interactions Phase Phenotype Piezo 1 ion channel Piezo 2 ion channel Population Process Proteomics Reporting Role Signal Pathway Signal Transduction Skin Societies Surface System Time Tissues Transgenic Organisms United States Work Wound models Xenograft Model adipocyte differentiation cell type cost data integration epigenomics functional loss healing image processing in vivo mechanical drive mechanical force mechanical signal mechanotransduction molecular dynamics molecular phenotype mortality mouse model multimodal data multiple omics new therapeutic target novel novel therapeutics prevent profibrotic fibroblast psychosocial regenerative response skin fibrosis skin regeneration skin wound skin xenograft small molecule subcutaneous therapeutic target transcriptomics translational goal treatment strategy wound wound care wound environment wound healing

项目摘要

7. Project Summary/Abstract Adult human skin heals by developing fibrotic scar tissue, which can result in devastating disfigurement, growth restriction, and permanent functional loss. Despite a plethora of clinical options, no current treatment strategies successfully prevent or reverse this fibrotic process, and scars and their sequelae cost the United States over $20 billion every year. Progress towards the development of new therapies has been significantly hindered by a lack of understanding of the cell populations responsible for scarring and their molecular dynamics. Studies in recent years have reported that adipocytes in wounds are capable of transitioning into fibroblasts (and vice versa); however, the extent to which adipocyte-to-fibroblast transition contributes to wound fibrosis (scarring), and whether this process can be targeted to prevent scarring, remain unknown. In this proposal, we explore for the first time the role of tissue mechanics in conversion of dermal adipocytes to scarring fibroblasts within the wound environment. First, employing genetic lineage tracing, we will use histology, immunohistochemistry, and flow cytometry to study adipocyte-to-fibroblast transition and to interrogate the molecular phenotype of adipocyte lineage-derived fibroblasts within wounds. Second, we will use a Rainbow mouse model to interrogate clonal dynamics of adipocyte-to-fibroblast transition in wounds, and will apply an integrated multi-omic analysis, with single-cell transcriptomic (scRNA-seq) and epigenomic (scATAC-seq), spatial transcriptomic (Visium) and proteomic (CODEX), and quantitative extracellular matrix (ECM) ultrastructural analyses, in order to robustly define the molecular drivers and pathways involved in adipocyte-to-fibroblast conversion during scarring. Third, as our preliminary data strongly support a mechanotransduction mechanism underlying adipocyte-to-fibroblast transition during wound healing, we will inhibit mechanical signaling in adipocytes using both small molecule and transgenic approaches in order to block adipocyte-to-fibroblast transition. We will apply a similar multi-omic analysis to elucidate the molecular dynamics that differentiate wound adipocyte dynamics in the context of intact versus blocked mechanical signaling and determine how inhibiting mechanically driven adipocyte-to-fibroblast conversion may reduce fibrosis and yield wound regeneration. Our ultimate translational goal is to develop therapeutics that target fibrogenic wound cell dynamics to promote regenerative healing. Collectively, the proposed work will significantly enhance our understanding of the key molecular and cellular determinants of cutaneous scarring, inform the development of novel anti-scarring therapies, and shed light on the contributions of adipose tissue to wound fibrosis.

7. 项目总结/摘要成人皮肤通过形成纤维化疤痕组织来愈合，这可能导致毁灭性的毁容、生长限制和永久性功能丧失。尽管临床选择众多，但目前尚无治疗策略成功地阻止或逆转这种纤维化过程，而疤痕及其后遗症使美国付出了超过每年200亿美元。新疗法的开发进展受到了严重阻碍缺乏对造成疤痕的细胞群及其分子动力学的了解。研究于近年来报道伤口中的脂肪细胞能够转变为成纤维细胞（反之亦然）反之亦然）；然而，脂肪细胞向成纤维细胞转变对伤口纤维化（疤痕）的影响程度，这一过程是否可以有针对性地防止疤痕形成，目前仍不得而知。在本提案中，我们探索首次揭示组织力学在真皮脂肪细胞向疤痕成纤维细胞转化中的作用伤口环境。首先，采用遗传谱系追踪，我们将使用组织学、免疫组织化学和流式细胞术研究脂肪细胞向成纤维细胞的转变并询问脂肪细胞的分子表型伤口内的谱系衍生的成纤维细胞。其次，我们将使用彩虹小鼠模型来询问克隆伤口中脂肪细胞向成纤维细胞转变的动力学，并将应用综合多组学分析，单细胞转录组 (scRNA-seq) 和表观基因组 (scATAC-seq)、空间转录组 (Visium) 和蛋白质组学 (CODEX) 和定量细胞外基质 (ECM) 超微结构分析，以便可靠地定义疤痕形成过程中脂肪细胞向成纤维细胞转化所涉及的分子驱动因素和途径。第三，因为我们的初步数据强烈支持脂肪细胞到成纤维细胞的机械转导机制在伤口愈合过程中的转变过程中，我们将使用小分子和转基因方法以阻止脂肪细胞向成纤维细胞的转变。我们将应用类似的多组学分析以阐明在完整的背景下区分伤口脂肪细胞动力学的分子动力学与受阻的机械信号传导相比，并确定如何抑制机械驱动的脂肪细胞向成纤维细胞的转变转化可以减少纤维化并促进伤口再生。我们的最终翻译目标是开发针对纤维化伤口细胞动力学以促进再生愈合的疗法。总的来说，拟议的工作将显着增强我们对关键分子和细胞决定因素的理解皮肤疤痕，为新型抗疤痕疗法的发展提供信息，并阐明贡献脂肪组织导致伤口纤维化。