Mechanisms of fibrosis in post-surgical lymphedema

术后淋巴水肿纤维化的机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该提议很重要，因为我们旨在开发用于次级淋巴水肿的新型治疗方法，这是一种常见和癌症治疗的病态并发症。这很重要，因为这种疾病的当前疗法是姑息和不足。在我们以前的研究中，我们已经表明淋巴水肿的病理是继发于进行性纤维化，并由慢性T-碳（CD4+）细胞炎症和T-助手2介导（TH2）分化。我们已经使用这些信息来开发新的疗法来治疗次级淋巴水肿，最近将我们的工作从板凳转换为调查员试验的床边使用Th2细胞因子中和抗体。该应用的目的是确定引发CD4+细胞炎症的细胞机制淋巴损伤后的反应。这个目标是我们以前工作的逻辑扩展，应确定可以针对药理学以治疗/预防淋巴水肿的其他靶标。我们的长期目标是利用我们从对淋巴水肿的基本理解中获得的信息来开发破坏的疗法促进进行性纤维化和淋巴功能障碍的事件的循环。我们的方法是创新的由于我们使用小鼠模型和临床标本的组合来剖析细胞机制淋巴水肿病理学。我们的小组的独特位置可以根据我们的基础来实现我们的目标多学科团队，我们进入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个特定目的的目标： AIM 1。确定淋巴损伤如何激活CD4+细胞。此目标将使用临床样本和鼠标测试角质形成细胞在CD4+细胞的激活和迁移中起关键作用的假设的模型淋巴瘤组织。此外，我们将检验以下假设：免疫中的单核苷酸多态性反应基因将增加淋巴水肿的风险。目标3。确定炎症如何损害淋巴功能。这个目标将检验以下假设淋巴水肿中的炎症反应损害了多种作用，包括组织和淋巴纤维化，疼痛炎症和副淋巴管的形成受损。

项目成果

期刊论文数量（57）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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
影响因子：
0
作者：
Kanapathy,Muholan;Patel,NikhilM;Kalaskar,DeepakM;Mosahebi,Afshin;Mehrara,BabakJ;Seifalian,AlexanderM
通讯作者：
Seifalian,AlexanderM

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
影响因子：
0
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

Regulation of lymphatic function and injury by nitrosative stress in obese mice.