Elucidating the Mechanisms of Lymphatic Muscle Cell Dysfunction in Aging and Inflammation

阐明衰老和炎症中淋巴肌细胞功能障碍的机制

基本信息

批准号：
10382881
负责人：
Howard Mark Kenney
金额：
$ 5.18万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2022-08-17 至 2024-10-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382881
关键词：
Actins Address Age Aging Alzheimer&apos s Disease Ankle Applications Grants Area Arthritis Atrophic Biology Blood Vessels Cardiovascular Diseases Cardiovascular system Caring Cell Lineage Cells Cellular biology Characteristics Chronic Clinical Clinical Trials Design Community Outreach Contracts Cytoskeletal Proteins Data Disease Disease Progression Down-Regulation Elderly Exhibits Failure Fluorescence-Activated Cell Sorting Fostering Foundations Frequencies Functional disorder Future Gene Expression Genes Genetic Transcription Glaucoma Goals Grant Hand Health Histology Homeostasis Image Immune response Indocyanine Green Inflammation Inflammatory Arthritis Inflammatory Bowel Diseases Joints Leadership Lymph Lymphatic Lymphatic System Lymphatic clearance Lymphatic function Lymphedema Lymphoid Tissue Measures Mediating Medical Metabolic Diseases Modeling Mus Muscle Cells Muscle Contraction Near-infrared optical imaging Neoplasm Metastasis Pathogenesis Pathology Pathway interactions Patients Physicians Publishing Recording of previous events Research Research Training Rest Rheumatoid Arthritis Role Scientific Inquiry Scientist Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Surface TNF gene Tamoxifen Targeted Research Testing Therapeutic Intervention Tissues Transgenic Mice Transgenic Organisms Universities Validation Vascular Smooth Muscle age related aged arthropathies cell type cohort differential expression experience frontier genetic signature human old age (65+)in vivo innovation lymphatic development lymphatic dysfunction lymphatic pump lymphatic vessel mortality mouse model novel pre-clinical research protein expression single-cell RNA sequencing success targeted treatment therapeutic target transcriptomics tumor

项目摘要

Project Summary/Abstract. Lymphatic dysfunction is known to be associated with various disorders involved in both aging and inflammation, such as Alzheimer’s disease, cardiovascular decline, and arthritic progression. Throughout aging, lymphatic contractility has been shown to deteriorate related to reduced gene expression of essential pathways that mediate homeostatic contractions and cytoskeletal integrity in lymphatic muscle cells (LMCs). Similarly, we previously discovered that age-dependent cellular mechanisms of lymphatic dysfunction in the tumor necrosis factor transgenic (TNF-Tg) mouse model of chronic inflammatory arthritis are associated with progression of joint disease and the loss of joint-draining popliteal lymphatic vessel (PLV) contractions in aged mice. In these aged mice, the PLV demonstrates significant LMC atrophy at an ultrastructural level, which is proposed to drive the elimination of lymphatic function and exacerbate disease progression. As a clinical correlate, we have found that patients with active rheumatoid arthritis have fewer functional LVs and diminished lymphatic clearance on the surface of the hands. Thus, we hypothesize that inflammation mediates accelerated age-related damage to LMCs where inflamed LMCs will exhibit a comparable dysfunction in the gene pathways necessary for LMC contractility and cytoskeletal integrity. To test this hypothesis, we propose to assess alpha smooth muscle actin (αSMA)+ PLV-LMC coverage and investigate transcriptional changes by single cell RNA sequencing (scRNAseq) in young (2-month-old), aged (8-month-old), and elderly (24-month- old) WT and TNF-Tg mice. Towards this goal, we have demonstrated that αSMA+ PLV-LMC coverage is reduced in aged (8-month-old) TNF-Tg mice relative to WT littermates. Additionally, we achieved preliminary success in scRNAseq of aged LMCs to indicate the feasibility of this approach. Given the inadequate characterization of LMCs necessary for targeted research into their role in health and disease, our scRNAseq data also provides evidence that LMCs are transcriptionally distinct vascular muscle cells. Through the completion of the research aims embodied in this grant proposal, we have the opportunity to provide considerable innovation for future pre-clinical research and targeted therapeutic interventions of LMCs. In line with the applicant’s Research Training Plan, the PI will gain valuable experience primarily in bench research with additional opportunities to foster abilities in clinical trial design, medical care, academic leadership, and community outreach at the University of Rochester with a cherished history of producing successful physician- scientists. For the following PA-21-049 F30 grant submission, we propose to elucidate the mechanisms of LMC dysfunction during both aging and inflammation for the benefit of lymphatic cellular biology and our understanding of the enigmatic age-related progression of arthritis.

项目摘要/摘要。众所周知，淋巴功能障碍与衰老和衰老相关的各种疾病有关。炎症，例如阿尔茨海默病、心血管衰退和关节炎进展。衰老，淋巴收缩力已被证明与必需基因表达减少有关介导淋巴肌细胞（LMC）稳态收缩和细胞骨架完整性的途径。同样，我们之前发现，淋巴功能障碍的年龄依赖性细胞机制慢性炎症性关节炎的肿瘤坏死因子转基因（TNF-Tg）小鼠模型与老年人关节疾病的进展和关节引流腘淋巴管（PLV）收缩的丧失在这些老年小鼠中，PLV 在超微结构水平上表现出显着的 LMC 萎缩。提出作为临床驱动消除淋巴功能和恶化疾病进展。相关联，我们发现活动性类风湿关节炎患者的功能性左心室较少，并且手表面的淋巴清除减少，因此，我们遭受了炎症介导的痛苦。加速 LMC 的年龄相关损伤，发炎的 LMC 将表现出类似的功能障碍为了检验这一假设，我们提出了 LMC 收缩性和细胞骨架完整性所必需的基因途径。评估 α 平滑肌肌动蛋白 (αSMA)+ PLV-LMC 覆盖范围并研究转录变化针对年轻人（2 个月大）、老年人（8 个月大）和老年人（24 个月大）的单细胞 RNA 测序 (scRNAseq) 为了实现这一目标，我们已经证明 αSMA+ PLV-LMC 覆盖率是旧的）WT 和 TNF-Tg 小鼠。此外，我们还初步实现了与 WT 同窝小鼠相比，老年（8 个月大）TNF-Tg 小鼠的 TNF-Tg 减少。鉴于存在的不足，老化 LMC 的 scRNAseq 的成功表明了这种方法的可行性。 LMC 的表征对于有针对性地研究它们在健康和疾病中的作用是必要的，我们的 scRNAseq 数据还提供证据表明 LMC 是转录上不同的血管肌细胞。完成本拨款提案中体现的研究目标，我们有机会提供为未来 LMC 的临床前研究和针对性治疗干预提供了巨大的创新。通过申请人的研究培训计划，PI将主要在实验室研究方面获得宝贵的经验有额外的机会培养临床试验设计、医疗保健、学术领导力和罗切斯特大学的社区外展工作有着培养成功医生的宝贵历史—— 对于以下 PA-21-049 F30 拨款申请，我们建议阐明 LMC 的机制。衰老和炎症过程中的功能障碍有利于淋巴细胞生物学和我们的了解关节炎与年龄相关的神秘进展。