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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.

项目摘要这一建议是重要的，因为我们的目标是开发新的治疗继发性水肿，一个常见的和癌症治疗的病态并发症。这一点很重要，因为目前对这种疾病的治疗是姑息和不足。在我们以前的研究中，我们已经表明，水肿的病理是继发于进行性纤维化，并由慢性T辅助细胞（CD 4+）炎症和T辅助细胞2介导 (Th2)分化我们利用这些信息开发了治疗继发性最近，在一项由医生发起的试验中，使用Th 2细胞因子中和抗体。本申请的目的是鉴定启动CD 4+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逻辑延伸，应确定可以靶向治疗/预防水肿的其他靶标。我们的长期目标是利用我们从对水肿的基本理解中获得的信息来开发治疗方法，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小鼠模型和临床标本的组合来剖析细胞机制，水肿病理学。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。我们计划实现我们使用2个具体目标的目标：目标1.确定淋巴损伤如何激活CD 4+细胞。这一目标将使用临床样本和小鼠模型来检验角质形成细胞在CD 4+细胞的活化和迁移中起关键作用的假设，水肿组织。此外，我们还将检验单核苷酸多态性在免疫系统中的作用这一假设。反应基因会增加水肿的风险。目标3.确定炎症如何损害淋巴功能。这一目标将检验以下假设：水肿中的炎症反应通过多种作用损害淋巴功能，包括组织和淋巴纤维化、淋巴管周围炎症和侧支淋巴管形成受损。

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）

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

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
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

Lymphedema and obesity: is there a link?

淋巴水肿和肥胖症：是否有联系？