权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10606927
负责人：
Babak J Mehrara
金额：
$ 23.36万
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：
2022
资助国家：
美国
起止时间：
2022-12-21 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606927
关键词：
Acidity Alkalinization American Animal Model Antibiotics Atopic Dermatitis Biopsy CD4 Positive T Lymphocytes Cells Chronic Clinical Deformity Deposition Dermis Developed Countries Development Disease Disease Progression Epidermis Functional disorder Goals Gynecologic High Prevalence Histologic Hospitalization Immune response Impairment Infectious Skin Diseases Infiltration Inflammation Inflammatory Inflammatory Response Injury Intravenous Kininogenase Knowledge Lymphatic Lymphedema Mediating Mediator Methods Mus Outcome PAR-2 Receptor Pain Palliative Care Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phase I Clinical Trials Physical therapy Play Positioning Attribute Pre-Clinical Model Prevention Proteins Quality of life Reaction Recurrence Risk Role Serine Protease Serine Proteinase Inhibitors Severity of illness Signal Pathway Skin Skin Abnormalities Skin Manifestations Solid Neoplasm Stains Stratum corneum Surgical complication Swelling T-Lymphocyte TSLP gene Testing Tissues Upper Extremity Urologic Cancer breast surgery cancer complication cancer therapy chronic inflammatory skin cytokine effective therapy functional disability iatrogenic injury improved inhibiting antibody innovation keratinocyte laboratory experience loss of function lymphatic pump lymphatic vessel malignant breast neoplasm melanoma mouse model novel palliative prevent recurrent infection reduce symptoms response sarcoma secondary lymphedema skin barrier skin disorder symptom treatment tumor urologic

项目摘要

PROJECT SUMMARY/ABSTRACT Secondary lymphedema is a common and dreaded disease that occurs in patients treated for a variety of solid tumors. An estimated 20–40% of Americans treated surgically for breast cancer, melanoma, gynecological or urologic tumors go on to develop lymphedema. Once the disease develops, it is usually progressive and causes significant functional impairment, recurrent infections, and decreased quality of life. Current treatments are palliative, aiming to treat symptoms and prevent progression rather than cure the underlying anatomic abnormalities. Thus, development of novel treatments for this disease is an important goal. Recent studies have shown that infiltration of T helper 2 (Th2)-differentiated CD4+ cells is an important mediator of lymphedema development by regulating fibroadipose tissue deposition, preventing formation of collateral lymphatics, decreasing lymphatic pumping, and causing lymphatic leakiness/dysfunction. However, the cellular mechanisms that activate these Th2 inflammatory responses remain unknown. In preliminary studies, we have found that the epidermis may play an important role in regulating Th2 inflammatory responses in lymphedema. For example, we have found that the expression of Th2-inducing cytokines— cytokines known to coordinate Th2 inflammation in other chronic skin disorders—is significantly increased by keratinocytes in lymphedematous tissues of patients with unilateral upper extremity lymphedema. We have also found that the expression of serine proteases, an important mechanism regulating Th2-inducing cytokine expression in other skin disorders, is also increased. Using mouse models, we have found that epidermal changes, including decreased expression of skin barrier proteins and of Th2-inducing cytokines, precedes infiltration of Th2 differentiated CD4+ cells. Based on these preliminary studies, as well as the pathophysiology of other Th2-mediated chronic skin disorders, we will test the hypothesis that impaired skin barrier function and skin pH regulate the expression of Th2-inducing cytokines by keratinocytes following lymphatic injury. Our study is innovative because the role of the epidermis has not been elucidated. This gap in our knowledge is important as epidermal changes are a prominent finding in lymphedema. We will test our hypothesis by analyzing skin barrier function, pH, and Th2-inducing cytokine expression in patients with unilateral breast cancer-related lymphedema. In other studies, we will use animal models to analyze the cellular mechanisms that regulate epidermal Th2-inducing cytokine expression and how these changes regulate the pathophysiology of lymphedema.

项目总结/文摘