Molecular mechanisms of age-related lymphatic dysfunction

年龄相关淋巴功能障碍的分子机制

• 批准号: 10538995
• 负责人: Babak J Mehrara
• 金额: $ 26.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538995
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aging; Alzheimer' s Disease; Anatomy; Animals; Antibodies; Apoptosis; Arthritis; Autoimmunity; Binding; Blood; Blood Vessels; Cardiovascular Diseases; Cell Differentiation process; Cell Proliferation; Cell Separation; Cell surface; Cells; Cholesterol Homeostasis; Chronic; Clinical; Elderly; Endothelial Cells; Event; Fatty Acids; Female; Functional disorder; Future; Goals; Growth Factor; Histamine Release; Histologic; Homologous Gene; Immune response; Impairment; In Vitro; Infection; Inflammation; Injury; Intestines; Knockout Mice; Ligands; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic clearance; Lymphatic function; Lymphedema; Mediating; Metabolic syndrome; Molecular; Mus; Muscle Cells; Neuraxis; Obesity; PIK3CG gene; PTEN gene; Pathologic; Pathway interactions; Phenotype; Phosphorylation; Physiological; Play; Pump; Reactive Nitrogen Species; Receptor Protein-Tyrosine Kinases; Recombinant Vascular Endothelial Growth Factor; Research; Research Design; Resolution; Role; Signal Transduction; Skin; Tamoxifen; Testing; Tissues; Transgenic Mice; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; adaptive immune response; age effect; age related; body system; conditional knockout; density; endothelial dysfunction; experimental study; improved; in vivo; innovation; lymphatic development; lymphatic dysfunction; lymphatic malformations; lymphatic pump; lymphatic vessel; macromolecule; male; mast cell; neutralizing antibody; nitrosative stress; novel; older patient; promoter; receptor; receptor binding; response; tumor

PROJECT SUMMARY/ABSTRACT Aging results in impaired lymphatic function in a variety of organ systems. This is important because the lymphatic system has many physiologic functions, and lymphatic abnormalities are implicated in many pathologic conditions that affect the elderly. However, while it is clear that aging impairs lymphatic function, the cellular mechanisms that regulate this response remain largely unknown. In addition, the effects of aging on lymphatic endothelial cell (LEC) response to vascular endothelial growth factor C (VEGFC), downstream pathways involving Pi3k and Akt signaling, and interactions with lymphatic muscle cells have not been analyzed. In previous and preliminary studies, we have found that chronic inflammation in a variety of settings, including obesity, lymphedema, and aging, results in decreased intracellular LEC Pi3K/Akt signaling. This is important since LEC Pi3K/Akt signaling is a key regulator of LEC proliferation, differentiation, and function. These findings are consistent with previous studies demonstrating that abnormalities in Pi3k/Akt signaling also contribute to age-related blood endothelial dysfunction. In this proposal, we aim to test the hypothesis that decreased LEC intracellular Pi3k/Akt signaling plays a causal role in age-related lymphatic dysfunction. Our study is innovative because previous studies have been largely observational and have not analyzed lymphangiogenic signaling in aging. We have also developed novel transgenic mice that enable us to selectively analyze the effects of changes in LEC intracellular Pi3k/Akt signaling, thus avoiding the limitations of previous studies that have relied on the systemic administration of recombinant VEGFC or VEGF-R3 antibodies. Using two aims, we will determine how aging changes LEC Pi3k/Akt signaling in different tissues and how these changes correlate with lymphatic function. These studies will help us determine how LECs respond to VEGFC in aging and how these changes modulate response to inflammation and nitrosative stress. In other studies, we will determine if inhibition of intracellular LEC Pi3k/Akt signaling in young mice can recapitulate the lymphatic phenotype of old mice. Finally, we will determine if increased LEC Pi3k/Akt signaling can improve lymphatic function in elderly mice. At the conclusion of our proposed research, we will have a detailed understanding of the cellular mechanisms that contribute to age-related lymphatic dysfunction. This understanding will provide the basis for future studies designed to improve lymphatic function.

项目摘要/摘要 衰老会导致各种器官系统中的淋巴功能受损。这很重要，因为 淋巴系统具有许多生理功能，淋巴异常与许多人有关 影响老年人的病理状况。但是，虽然很明显衰老会损害淋巴功能，但 调节这种反应的细胞机制在很大程度上仍然未知。另外，衰老对 淋巴内皮细胞（LEC）对血管内皮生长因子C（VEGFC），下游的反应 涉及PI3K和AKT信号传导以及与淋巴肌肉细胞的相互作用的途径尚未 分析。 在以前的和初步研究中，我们发现在各种环境中的慢性炎症， 包括肥胖，淋巴水肿和衰老，导致细胞内LEC PI3K/AKT信号降低。这是 重要的是因为LEC PI3K/AKT信号传导是LEC增殖，分化和功能的关键调节剂。 这些发现与以前的研究一致，表明PI3K/AKT信号的异常也是如此 导致与年龄相关的血液内皮功能障碍。在此提案中，我们旨在检验以下假设。 LEC细胞内PI3K/AKT信号传导在与年龄相关的淋巴功能障碍中起因果作用。 我们的研究具有创新性，因为以前的研究在很大程度上是观察性的，没有 分析的淋巴管原性信号传导。我们还开发了新颖的转基因小鼠，使我们能够 有选择地分析LEC细胞内PI3K/AKT信号的变化的影响，从而避免了局限性 在以前依赖重组VEGFC或VEGF-R3的系统给药的研究中 抗体。使用两个目标，我们将确定衰老如何改变不同组织中的LEC PI3K/AKT信号 以及这些变化与淋巴功能的相关性。这些研究将帮助我们确定LEC如何 对衰老中的VEGFC响应以及这些变化如何调节对炎症和亚硝化应激的反应。 在其他研究中，我们将确定年轻小鼠中细胞内LEC PI3K/AKT信号的抑制是否可以 概括旧小鼠的淋巴表型。最后，我们将确定是否增加了LEC PI3K/AKT信号传导 可以改善老年小鼠的淋巴功能。 在我们提出的研究结束时，我们将对细胞有详细的了解 导致与年龄相关的淋巴功能障碍的机制。这种理解将为 未来的研究旨在改善淋巴功能。