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

基本信息

  • 批准号:
    8372995
  • 负责人:
  • 金额:
    $ 77.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Lymphedema is the accumulation of protein rich fluid in tissues, and in the US, occurs most commonly as a surgical complication of cancer treatment. Despite the fact that 3-5 million Americans suffer from lymphedema, its etiology is unknown and treatment remains palliative. Based on our laboratory data as well as the clinical presentation of lymphedema we hypothesize that the pathology of lymphedema is secondary to progressive fibrosis and is mediated by chronic T-helper (CD4+) cell inflammation. The objective of this proposal is to determine how lymphatic fluid stasis causes tissue fibrosis and lymphatic dysfunction. Our long-term objective is to develop therapies to treat or prevent lymphedema by disrupting the cycle of stasis, fibrosis, and lymphatic dysfunction. This approach is innovative since previous efforts have attempted to treat lymphedema by augmenting lymphatic repair and regeneration using cytokines. These cytokines, however, can also cause tumor metastasis or recurrence thereby limiting the applicability of this approach in cancer patients. This proposal is relevant since lymphedema is a common and morbid complication of cancer treatment for which there is no proven preventative methods and treatment is palliative. We plan to achieve our objectives using 3 specific aims. Aim 1: Determine the cellular sources of profibrotic cytokines. This aim will test the working hypothesis that CD4+ T-cells are the primary source of profibrotic cytokines using transgenic mice, antibody depletion, and adoptive transfer experiments in a mouse-tail and axillary dissection model. Aim 2: Determine how the expression of profibrotic cytokines is regulated. This aim will test the working hypothesis is that lymphatic stasis causes Th2 cell inflammation and IL4 and IL13 expression and that these cytokines interact to cause fibrosis and lymphatic dysfunction. We will use clinical specimens from patients with lymphedema before and after medical or surgical treatment as well as our mouse tail model. Aim 3: Determine how profibrotic cytokines regulate lymphatic function and fibrosis. This aim will test the working hypothesis that impaired lymphatic function secondary to fibrosis is a consequence of indirect effects of T-cells and Th2 cytokines on the lymphatic system rather than down-regulation of lymphangiogenic cytokine expression. PUBLIC HEALTH RELEVANCE: This application is relevant and in-line with the mission of the NIH since we aim to identify the basic pathophysiology of a common and disabling complication of cancer treatment. This information can be used to design targeted, rational treatments and preventative strategies that are oncologically safe. In addition, our research has broader relevance as it will increase our understanding of the lymphatic system which plays a critical role in fat metabolism, immunity, inflammation, and tumor metastasis.
描述(由申请人提供):淋巴水肿是组织中富含蛋白质的液体的积聚,在美国,最常见的是癌症治疗的手术并发症。尽管有3-5百万美国人患有水肿,但其病因尚不清楚,治疗仍然是姑息性的。根据我们的实验室数据以及水肿的临床表现,我们假设水肿的病理学继发于进行性纤维化,并由慢性T辅助细胞(CD 4+)炎症介导。本提案的目的是确定淋巴液淤滞如何导致组织纤维化和淋巴功能障碍。我们的长期目标是通过破坏停滞、纤维化和淋巴功能障碍的循环来开发治疗或预防水肿的疗法。这种方法是创新的,因为先前的努力试图通过使用细胞因子增强淋巴修复和再生来治疗水肿。然而,这些细胞因子也可引起肿瘤转移或复发,从而限制了该方法在癌症患者中的适用性。这项建议是 相关,因为水肿是癌症治疗的常见和病态并发症,对于其没有经证实的预防方法,并且治疗是姑息性的。我们计划通过三个具体目标来实现我们的目标。目的1:确定促纤维化细胞因子的细胞来源。这一目的将使用转基因小鼠、抗体耗竭和小鼠尾和腋窝解剖模型中的过继转移实验来检验工作假设,即CD 4 + T细胞是促纤维化细胞因子的主要来源。目的2:确定促纤维化细胞因子的表达是如何调节的。这一目的将测试工作假设,即淋巴停滞导致Th 2细胞炎症和IL 4和IL 13表达,并且这些细胞因子相互作用导致纤维化和淋巴功能障碍。我们将使用来自内科或外科治疗前后的水肿患者的临床标本以及我们的小鼠尾模型。目的3:确定促纤维化细胞因子如何调节淋巴功能和纤维化。这一目的将测试工作假设,即继发于纤维化的淋巴功能受损是T细胞和Th 2细胞因子对淋巴系统的间接作用的结果,而不是淋巴管生成细胞因子表达的下调。 公共卫生关系:本申请与NIH的使命相关并符合NIH的使命,因为我们的目标是确定癌症治疗常见和致残并发症的基本病理生理学。这些信息可用于设计有针对性的,合理的治疗和预防策略,是肿瘤安全的。此外,我们的研究具有更广泛的相关性,因为它将增加我们对淋巴系统的理解,淋巴系统在脂肪代谢,免疫,炎症和肿瘤转移中起着关键作用。

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(4)

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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:
    $ 77.95万
  • 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:
    10538995
  • 财政年份:
    2022
  • 资助金额:
    $ 77.95万
  • 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:
    $ 77.95万
  • 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:
    $ 77.95万
  • 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:
    $ 77.95万
  • 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:
    $ 77.95万
  • 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:
    $ 77.95万
  • 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:
    $ 77.95万
  • 项目类别:
Surgical Oncology Research Training Grant
肿瘤外科研究培训补助金
  • 批准号:
    10456823
  • 财政年份:
    1984
  • 资助金额:
    $ 77.95万
  • 项目类别:
Surgical Oncology Research Training Grant
肿瘤外科研究培训补助金
  • 批准号:
    10674795
  • 财政年份:
    1984
  • 资助金额:
    $ 77.95万
  • 项目类别:

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