Mechanisms of fibrosis in post-surgical lymphedema

术后淋巴水肿纤维化的机制

• 批准号: 10063531
• 负责人: Babak J Mehrara
• 金额: $ 89.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063531
• 关键词: Animal Model; Animals; Antigens; Award; Axillary Lymph Node Dissection; B-Lymphocytes; Bacterial Antigens; Biopsy Specimen; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; Clinical; Clone Cells; Dendritic Cells; Development; Disease; Disease Progression; Estrogens; Event; Extracellular Matrix; Female; Fibrosis; Formulation; Functional disorder; Generations; Goals; Immune Response Genes; Immune response; Immunity; Immunology; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Knowledge; Lead; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Lymphedema; Mastectomy; Mediating; Mission; Modeling; Neoplasm Metastasis; Nitric Oxide; Nitrogen; Operative Surgical Procedures; Oxidative Stress; Oxygen; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Play; Podoconiosis; Positioning Attribute; Prevention strategy; Process; Publications; Publishing; Reaction; Research; Risk; Role; Sampling; Secondary to; Severities; Signal Transduction; Single Nucleotide Polymorphism; Skin; Source; Specimen; Surgical Injuries; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Testing; Tissues; Topical application; Transforming Growth Factor beta; Transgenic Animals; Translating; United States National Institutes of Health; Work; autoreactive T cell; base; bench to bedside; cancer cell; cancer complication; cancer therapy; cardiovascular injury; chemokine; clinical practice; clinically relevant; cytokine; design; efficacy study; event cycle; first-in-human; genome wide association study; high risk; immunotherapy trials; innovation; investigator-initiated trial; keratinocyte; lipid metabolism; lymphatic dysfunction; lymphatic vasculature; lymphatic vessel; macrophage; male; migration; mouse model; multidisciplinary; neutralizing antibody; novel; novel therapeutics; palliative; pre-clinical; prevent; repaired; response; secondary lymphedema; skin disorder; small molecule inhibitor; therapy development; treatment strategy; tumor

Project Summary This proposal is significant because we aim to develop novel treatments for secondary lymphedema, a common and morbid complication of cancer treatment. This is important because current therapies for this disease are palliative and inadequate. In our previous studies, we have shown that the pathology of lymphedema is secondary to progressive fibrosis and is mediated by chronic T-helper (CD4+) cell inflammation and T-helper 2 (Th2) differentiation. We have used this information to develop novel therapies for the treatment of secondary lymphedema and have recently translated our work from the bench to the bedside in an investigator-initiated trial using Th2 cytokine neutralizing antibodies. The objective of this application is to identify the cellular mechanisms that initiate CD4+ cell inflammatory responses following lymphatic injury. This objective is a logical extension of our previous work and should identify additional targets that can be targeted pharmacologically to treat/prevent lymphedema. Our long-term objective is to use the information we gain from this basic understanding of lymphedema to develop therapies that disrupt the cycle of events that promote progressive fibrosis and lymphatic dysfunction. Our approach is innovative since we use a combination of mouse models and clinical specimens to dissect the cellular mechanisms of lymphedema pathology. Our group is uniquely positioned to accomplish our goals on the basis of our multidisciplinary team, our access to clinical tissues, and our novel mouse models. We plan to achieve our objectives using 2 specific aims: Aim 1. Determine how lymphatic injury activates CD4+ cells. This aim will use clinical samples and mouse models to test the hypothesis that keratinocytes play a key role in the activation and migration of CD4+ cells to lymphedematous tissues. In addition, we will test the hypothesis that single nucleotide polymorphisms in immune response genes will increase the risk of lymphedema. Aim 3. Determine how inflammation impairs lymphatic function. This aim will test the hypothesis that inflammatory responses in lymphedema impair lymphatic function by multiple effects, including tissue and lymphatic fibrosis, perilymphatic inflammation, and impaired formation of collateral lymphatic vessels.

项目摘要 这项建议意义重大，因为我们的目标是开发新的治疗继发性淋巴水肿的方法，这是一种常见的 以及癌症治疗的病态并发症。这一点很重要，因为目前治疗这种疾病的方法是 治标不治本，不称职。在我们之前的研究中，我们已经表明淋巴水肿的病理是 继发于进行性纤维化，由慢性辅助性T细胞炎症和辅助性T细胞2介导 (Th2)分化。我们已经利用这些信息开发了治疗继发性心脏病的新疗法。 淋巴水肿，最近在一项由研究人员发起的试验中将我们的工作从替补席上转移到了床边 使用Th2细胞因子中和抗体。 这项应用的目的是确定启动CD4+细胞炎症的细胞机制。 淋巴损伤后的反应。这一目标是我们以前工作的合乎逻辑的延伸，应该确定 可通过药物靶点治疗/预防淋巴水肿的其他靶点。我们的长期目标 是利用我们从淋巴水肿的基本理解中获得的信息来开发扰乱 促进进行性纤维化和淋巴功能障碍的事件循环。我们的方法是创新的 由于我们使用了小鼠模型和临床标本相结合的方法来剖析 淋巴水肿病理。我们的集团处于独特的地位，可以在我们的基础上实现我们的目标 多学科团队，我们对临床组织的访问，以及我们的新型小鼠模型。我们计划实现我们的 使用2个特定目标的目标： 目的1.确定淋巴损伤如何激活CD4+细胞。这一目标将使用临床样本和小鼠 验证角质形成细胞在CD4+细胞活化和迁移中发挥关键作用的假设的模型 淋巴水肿性组织。此外，我们将检验单核苷酸多态在免疫中的假设 反应基因会增加淋巴水肿的风险。 目的3.确定炎症如何损害淋巴功能。这一目标将检验这一假设 淋巴水肿中的炎症反应通过多种影响损害淋巴功能，包括组织和 淋巴管纤维化、淋巴管周围炎症和侧支淋巴管形成障碍。

项目成果

Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

• DOI: 10.1038/jid.2015.283
• 发表时间: 2015-11
• 期刊: The Journal of investigative dermatology
• 作者: Savetsky IL;Albano NJ;Cuzzone DA;Gardenier JC;Torrisi JS;García Nores GD;Nitti MD;Hespe GE;Nelson TS;Kataru RP;Dixon JB;Mehrara BJ
• 通讯作者: Mehrara BJ

A Prospective Study on the Safety and Efficacy of Vascularized Lymph Node Transplant.

一项关于血管化淋巴结移植的安全性和有效性的前瞻性研究。

• DOI: 10.1097/sla.0000000000005591
• 发表时间: 2022-10-01
• 期刊: Annals of surgery
• 影响因子: 9

Tissue-engineered lymphatic graft for the treatment of lymphedema.

用于治疗淋巴水肿的组织工程淋巴移植物。

• DOI: 10.1016/j.jss.2014.07.059
• 发表时间: 2014
• 期刊: The Journal of surgical research
• 作者: Kanapathy,Muholan;Patel,NikhilM;Kalaskar,DeepakM;Mosahebi,Afshin;Mehrara,BabakJ;Seifalian,AlexanderM
• 通讯作者: Seifalian,AlexanderM

Lymphedema and obesity: is there a link?

淋巴水肿和肥胖症：是否有联系？

• DOI: 10.1097/prs.0000000000000268
• 发表时间: 2014-07
• 期刊: Plastic and reconstructive surgery
• 影响因子: 3.6
• 作者: Mehrara BJ;Greene AK
• 通讯作者: Greene AK

Lymphatic Contribution to the Cellular Niche in Heterotopic Ossification.

• DOI: 10.1097/sla.0000000000001619
• 发表时间: 2016-12
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Loder S;Agarwal S;Sorkin M;Breuler C;Li J;Peterson J;Gardenier J;Hsieh HH;Wang SC;Mehrara BJ;Levi B
• 通讯作者: Levi B