Molecular mechanisms of age-related lymphatic dysfunction
年龄相关淋巴功能障碍的分子机制
基本信息
- 批准号:10538995
- 负责人:
- 金额:$ 26.55万
- 依托单位:
- 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:2022-07-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAffectAgingAlzheimer&aposs DiseaseAnatomyAnimalsAntibodiesApoptosisArthritisAutoimmunityBindingBloodBlood VesselsCardiovascular DiseasesCell Differentiation processCell ProliferationCell SeparationCell surfaceCellsCholesterol HomeostasisChronicClinicalElderlyEndothelial CellsEventFatty AcidsFemaleFunctional disorderFutureGoalsGrowth FactorHistamine ReleaseHistologicHomologous GeneImmune responseImpairmentIn VitroInfectionInflammationInjuryIntestinesKnockout MiceLigandsLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic SystemLymphatic clearanceLymphatic functionLymphedemaMediatingMetabolic syndromeMolecularMusMuscle CellsNeuraxisObesityPIK3CG genePTEN genePathologicPathway interactionsPhenotypePhosphorylationPhysiologicalPlayPumpReactive Nitrogen SpeciesReceptor Protein-Tyrosine KinasesRecombinant Vascular Endothelial Growth FactorResearchResearch DesignResolutionRoleSignal TransductionSkinTamoxifenTestingTissuesTransgenic MiceVascular Endothelial Growth Factor CVascular Endothelial Growth Factorsadaptive immune responseage effectage relatedbody systemconditional knockoutdensityendothelial dysfunctionexperimental studyimprovedin vivoinnovationlymphatic developmentlymphatic dysfunctionlymphatic malformationslymphatic pumplymphatic vesselmacromoleculemalemast cellneutralizing antibodynitrosative stressnovelolder patientpromoterreceptorreceptor bindingresponsetumor
项目摘要
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的淋巴功能受损。这一点很重要,因为
淋巴系统有许多生理功能,淋巴异常与许多
影响老年人的病态疾病。然而,尽管衰老显然会损害淋巴功能,但
调控这种反应的细胞机制在很大程度上仍不清楚。此外,老化对
淋巴管内皮细胞(LEC)对血管内皮生长因子C(VEGFC)下游的反应
涉及PI3K和Akt信号以及与淋巴肌细胞相互作用的通路尚未得到
分析过了。
在之前和初步的研究中,我们发现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信号减少。这是
重要的是因为LEC PI3K/Akt信号是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表明,PI3K/Akt信号的异常也是一致的
导致年龄相关的血管内皮细胞功能障碍。在这个提案中,我们的目标是检验这样一个假设
LEC细胞内PI3K/Akt信号降低在年龄相关性淋巴功能障碍中起一定作用。
我们的研究是创新的,因为以前的研究主要是观察性的,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信号变化的影响,从而避免限制
以前的研究依赖于重组VEGFC或VEGF-R3的系统给药
抗体。利用两个目标,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关系。这些研究将帮助我们确定LEC是如何
在衰老过程中对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,我们将确定抑制幼鼠细胞内LEC PI3K/Akt信号是否可以
重述老年小鼠的淋巴表型。最后,我们将确定LEC PI3K/Akt信号是否增加
能改善老年小鼠的淋巴功能。
在我们拟议的研究结束时,我们将对细胞
导致年龄相关性淋巴功能障碍的机制。这一理解将为
未来旨在改善淋巴功能的研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Babak J Mehrara其他文献
Babak J Mehrara的其他文献
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{{ truncateString('Babak J Mehrara', 18)}}的其他基金
Role of epidermis in regulating inflammatory skin manifestations of post-surgical lymphedema
表皮在调节术后淋巴水肿炎症性皮肤表现中的作用
- 批准号:
10606927 - 财政年份:2022
- 资助金额:
$ 26.55万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 26.55万 - 项目类别:
Restoration of lymphatic function in postsurgical lymphedema with lymph node transfer
通过淋巴结转移恢复术后淋巴水肿的淋巴功能
- 批准号:
9185953 - 财政年份:2015
- 资助金额:
$ 26.55万 - 项目类别:
Mechanisms of fibrosis and lymphatic dysfunction in post-surgical lymphedema
术后淋巴水肿纤维化和淋巴功能障碍的机制
- 批准号:
8532029 - 财政年份:2012
- 资助金额:
$ 26.55万 - 项目类别:
Mechanisms of fibrosis in post-surgical lymphedema
术后淋巴水肿纤维化的机制
- 批准号:
10063531 - 财政年份:2012
- 资助金额:
$ 26.55万 - 项目类别:
Mechanisms of fibrosis and lymphatic dysfunction in post-surgical lymphedema
术后淋巴水肿纤维化和淋巴功能障碍的机制
- 批准号:
8372995 - 财政年份:2012
- 资助金额:
$ 26.55万 - 项目类别:
Mechanisms of fibrosis and lymphatic dysfunction in post-surgical lymphedema
术后淋巴水肿纤维化和淋巴功能障碍的机制
- 批准号:
8695460 - 财政年份:2012
- 资助金额:
$ 26.55万 - 项目类别:
Mechanisms of fibrosis and lymphatic dysfunction in post-surgical lymphedema
术后淋巴水肿纤维化和淋巴功能障碍的机制
- 批准号:
9094645 - 财政年份:2012
- 资助金额:
$ 26.55万 - 项目类别:
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