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: 10665795
• 负责人: Babak J Mehrara
• 金额: $ 22.13万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665795
• 关键词: 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; Central Nervous System; Cholesterol Homeostasis; Chronic; Clinical; Cytoprotection; 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; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic clearance; Lymphatic function; Lymphedema; Mediating; Metabolic syndrome; Molecular; Mus; Muscle Cells; Obesity; PIK3CG gene; PTEN gene; Pathologic; Pathway interactions; Phenotype; Phosphorylation; Physiological; Play; Proliferating; 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 Factor Receptor-3; 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.

项目概要/摘要 衰老会导致多种器官系统的淋巴功能受损。这很重要，因为 淋巴系统具有许多生理功能，淋巴异常与许多疾病有关 影响老年人的病理状况。然而，虽然衰老会损害淋巴功能是显而易见的，但 调节这种反应的细胞机制仍然很大程度上未知。此外，衰老对 淋巴管内皮细胞 (LEC) 对下游血管内皮生长因子 C (VEGFC) 的反应 涉及 Pi3k 和 Akt 信号传导以及与淋巴肌细胞相互作用的途径尚未被研究 分析了。 在之前和初步的研究中，我们发现各种情况下的慢性炎症， 包括肥胖、淋巴水肿和衰老，导致细胞内 LEC Pi3K/Akt 信号传导减少。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因子。 这些发现与之前的研究一致，表明 Pi3k/Akt 信号传导异常也 导致与年龄相关的血液内皮功能障碍。在这个提案中，我们的目的是检验以下假设： LEC 细胞内 Pi3k/Akt 信号传导减少在与年龄相关的淋巴功能障碍中起着因果作用。 我们的研究具有创新性，因为之前的研究主要是观察性的，并没有 分析了衰老过程中的淋巴管生成信号。我们还开发了新型转基因小鼠，使我们能够 选择性分析 LEC 细胞内 Pi3k/Akt 信号传导变化的影响，从而避免局限性 之前依赖重组 VEGFC 或 VEGF-R3 全身给药的研究 抗体。通过两个目标，我们将确定衰老如何改变不同组织中的 LEC Pi3k/Akt 信号传导 以及这些变化如何与淋巴功能相关。这些研究将帮助我们确定 LEC 如何 衰老过程中对 VEGFC 的反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，我们将确定抑制年轻小鼠的细胞内 LEC Pi3k/Akt 信号传导是否可以 重现老年小鼠的淋巴表型。最后，我们将确定 LEC Pi3k/Akt 信号传导是否增加 可以改善老年小鼠的淋巴功能。 在我们提出的研究结束时，我们将对细胞有一个详细的了解 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。