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.

项目总结/摘要 衰老导致各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，并且淋巴异常与许多疾病有关。 影响老年人的病理状况。然而，虽然很明显，老化损害淋巴功能， 调节这种反应的细胞机制在很大程度上仍然是未知的。此外，衰老对 淋巴管内皮细胞（LEC）对血管内皮生长因子C（VEGFC）的反应，下游 涉及Pi 3 k和Akt信号传导的途径，以及与淋巴肌细胞的相互作用尚未被证实。 分析了 在以前的初步研究中，我们发现在各种情况下的慢性炎症， 包括肥胖、水肿和衰老，导致细胞内LEC Pi 3 K/Akt信号传导减少。这是 这是重要的，因为LEC Pi 3 K/Akt信号传导是LEC增殖、分化和功能的关键调节剂。 这些发现与先前的研究一致，表明Pi 3 k/Akt信号传导的异常也 有助于与年龄相关的血液内皮功能障碍。在这个提议中，我们的目标是测试假设， LEC细胞内Pi 3 k/Akt信号转导的减少在年龄相关的淋巴功能障碍中起着因果作用。 我们的研究是创新的，因为以前的研究主要是观察性的， 分析了衰老过程中的淋巴管生成信号。我们还开发了新的转基因小鼠，使我们能够 选择性地分析LEC细胞内Pi 3 k/Akt信号通路变化的影响，从而避免了限制 依赖于重组VEGFC或VEGF-R3全身给药的先前研究 抗体的使用两个目标，我们将确定衰老如何改变不同组织中LEC Pi 3 k/Akt信号转导 以及这些变化与淋巴功能的关系。这些研究将帮助我们确定LEC 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，我们将确定在年轻小鼠中抑制细胞内LEC Pi 3 k/Akt信号传导是否可以 重现老年小鼠的淋巴表型。最后，我们将确定增加的LEC Pi 3 k/Akt信号传导是否 可以改善老年小鼠的淋巴功能。 在我们提出的研究结论，我们将有一个详细的了解细胞 导致年龄相关淋巴功能障碍的机制。这一理解将为 未来的研究旨在改善淋巴功能。