Retinoic Acid Induced Lymphangiogenesis for Post-surgical Lymphedema

视黄酸诱导淋巴管生成治疗术后淋巴水肿

• 批准号: 10472024
• 负责人: Alex K. Wong
• 金额: $ 62.67万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472024
• 关键词: Address; Affect; American; Biology; Blood Vessels; Carrier Proteins; Cell Differentiation process; Cell Proliferation; Chronic; Clinical; Clinical Treatment; Cues; Development; Devices; Diagnostic; Differentiation and Growth; Dimerization; Disease; Drainage procedure; Endothelial Cells; Etiology; Excision; Exposure to; FGFR3 gene; FGFR4 gene; Fibroblast Growth Factor Receptors; Fibrosis; Functional disorder; Growth; Hour; Hyaluronic Acid; Immune System Diseases; In Vitro; Individual; Infection; Injury; Intercellular Fluid; KDR gene; Laboratories; Limb structure; Liquid substance; Lymph Node Dissections; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Obstruction; Lymphedema; Malignant Neoplasms; Measures; Mediating; Molecular; Natural regeneration; Nuclear Receptors; Operative Surgical Procedures; PPAR gamma; Pathway interactions; Patients; Pelvic Cancer; Pharmacology; Pharmacotherapy; Plastic Surgeon; Pre-Clinical Model; Preventive treatment; Quality of life; RXR; Receptor Protein-Tyrosine Kinases; Recurrence; Risk; Rodent Model; Role; Sampling; Sensitivity and Specificity; Signal Transduction; Skin; Solid Neoplasm; Spectrum Analysis; Surgical Injuries; Swelling; System; Techniques; Technology; Testing; Therapeutic; Tissues; Treatment Protocols; Tretinoin; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Vitamin A; Work; alitretinoin; angiogenesis; base; cell growth; cell type; cellular retinoic acid binding protein II; clinical care; clinical translation; disability; early detection biomarkers; effective therapy; experimental study; fatty acid-binding proteins; improved; in vivo; inhibitor; lymph nodes; lymphatic circulation; lymphatic drainage; lymphatic insufficiency; lymphatic vessel; malignant breast neoplasm; melanoma; migration; minimally invasive; pre-clinical; predictive modeling; prevent; promoter; receptor; recurrent infection; regeneration following injury; response; retinoic acid receptor alpha; sarcoma; secondary lymphedema; selective expression; side effect; small molecule inhibitor; soft tissue; translational framework; urologic

Lymphedema is an incurable condition characterized by lymphatic obstruction, tissue swelling, immune dysfunction, and fibrosis after lymphatic injury. Lymphedema affects 5 million Americans and is associated with poor quality of life due to extremity disability, disfigurement, and risk for recurrent limb-threatening infection. In the US, lymphedema is most commonly a consequence of lymph node dissection for the treatment of solid tumors such as breast or pelvic cancer. Despite the fact that lymphedema is common and morbid, there are currently no effective drug treatments. Using preclinical rodent models of lymphedema, we have shown that 9-cis retinoic acid (RA) significantly accelerates lymphatic regeneration following injury, restores functional lymphatic drainage, and prevents development of lymphedema. Our overarching hypothesis is that RA-mediated lymphangiogenesis is a promising therapy for secondary lymphedema. The objective of this proposal, which is the first logical step towards implementing this treatment clinically, is to increase our understanding of the mechanisms by which RAs regulate lymphangiogenesis and develop a translational framework for the use of these compounds. The specific aims of this proposal include Aim 1: Determine how RA selectively induces lymphangiogenesis; Aim 2: Elucidate the roles of FGFR and VEGFR signaling in RA-mediated lymphangiogenesis; and Aim 3: Use early biomarkers of lymphatic insufficiency to develop a predictive model that can guide initiation of RA therapy. Based on the current lack of effective therapy, it is clear that there is a need to develop an etiology-focused treatment for post-surgical lymphedema. The proposed studies will address important mechanistic questions regarding RA mediated lymphangiogenesis and also develop an early biomarker based predictive model that will guide treatment windows for RA therapy. The proposed work will significantly improve our understanding of RA-mediated lymphangiogenesis as well as support clinical translation of a RA as a preventative treatment regimen for post-surgical lymphedema.

淋巴水肿是一种无法治愈的疾病，其特征是淋巴阻塞、组织肿胀、 免疫功能障碍以及淋巴损伤后的纤维化。淋巴水肿影响 500 万美国人 由于四肢残疾、毁容和复发风险，与生活质量差有关 威胁肢体的感染。在美国，淋巴水肿最常见是淋巴结引起的 用于治疗实体瘤（例如乳腺癌或盆腔癌）的解剖。尽管事实上 淋巴水肿是一种常见病态，目前尚无有效的药物治疗方法。使用 在淋巴水肿的临床前啮齿动物模型中，我们发现 9-顺式视黄酸 (RA) 显着 加速受伤后的淋巴再生，恢复功能性淋巴引流，以及 防止淋巴水肿的发展。我们的首要假设是 RA 介导 淋巴管生成是继发性淋巴水肿的一种有前景的治疗方法。该提案的目标， 这是在临床上实施这种治疗的第一个合乎逻辑的步骤，就是增加我们的 了解 RA 调节淋巴管生成的机制并开发 使用这些化合物的翻译框架。该提案的具体目标包括 目标 1：确定 RA 如何选择性诱导淋巴管生成；目标 2：阐明 FGFR 的作用 RA 介导的淋巴管生成中的 VEGFR 信号传导；目标 3：使用早期生物标志物 淋巴功能不全，以开发可以指导 RA 治疗开始的预测模型。基于 鉴于目前缺乏有效的治疗方法，显然有必要开发一种针对病因的治疗方法 治疗术后淋巴水肿。拟议的研究将解决重要的机制 关于 RA 介导的淋巴管生成的问题，并开发基于早期生物标记的 预测模型将指导 RA 治疗的治疗窗口。拟议的工作将 显着提高我们对 RA 介导的淋巴管生成的理解并支持临床 将 RA 转化为术后淋巴水肿的预防性治疗方案。