Investigation of 9-cis Retinoic Acid as a Novel Treatment for Post-Surgical Lymphedema

9-顺式视黄酸作为术后淋巴水肿新疗法的研究

• 批准号: 9243806
• 负责人: Alex K. Wong
• 金额: $ 17.8万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243806
• 关键词: AIDS with Kaposi' s sarcoma; Adjuvant Radiotherapy; Adverse effects; Affect; Animal Model; Animals; Binding; Blood Vessels; Breast; Cancer Survivorship; Cell Cycle Checkpoint; Cell Proliferation; Clinical; Clinical Trials; Compression Bandage; Cosmetics; Data; Defect; Development; Development Plans; Disease; Disease Progression; Disease model; Distal; Doctor of Philosophy; Dose; Excision; FDA approved; FGFR3 gene; Fibroblast Growth Factor Receptors; Functional disorder; Funding; Genitourinary system; Goals; Grant; Green Fluorescent Proteins; Growth Factor; Hindlimb; Histologic; Human; In Vitro; Incidence; Individual; Infection; Injury; International; Investigation; Knowledge; Laboratories; Lead; Limb structure; Link; Liquid substance; Lymph; Lymph node excision; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphedema; Maintenance; Malignant Neoplasms; Manual Lymphatic Drainage; Measures; Mediating; Medical; Mentors; Modality; Molecular Analysis; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Pelvis; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Plant Roots; Play; Principal Investigator; Pump; Quality of life; Rattus; Receptor Signaling; Recurrence; Reporter; Reporting; Reproducibility; Research Personnel; Risk; Scientist; Series; Shunt Device; Signal Transduction; Solid; Surgeon; Surgical Flaps; Surgical Models; Swelling; System; Therapeutic; Time; Tissue Donors; Tissues; Transgenic Organisms; Tretinoin; United States; United States National Institutes of Health; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factors; Venous; Work; alitretinoin; base; career development; clinical effect; density; disability; improved; in vivo; knockout animal; lymph flow; lymph nodes; meetings; mouse model; novel; peptide P3; pre-clinical; prevent; promoter; reduce symptoms; skin lesion; small molecule; translation to humans; translational study; tumor

Project Summary/Abstract Lymphedema is an incurable condition characterized by tissue swelling after lymphatic damage. It affects over 140 million individuals worldwide 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 usually due to lymph node resection in association with the treatment of malignancies such as breast or pelvic tumors. There are currently no known medical therapies that can prevent or reverse the clinical progression of lymphedema in humans. However, recent data suggests that surgical transfer of vascularized lymph nodes (VLN) to replace damaged lymph nodes or divert lymphatic flow from a distal extremity may limit and even reverse disease progression. Since lymphatic damage and backflow is the root cause of lymphedema, we hypothesize that exogenous stimulation of lymphangiogenesis at the time of the initiating lymphatic injury may be an effective strategy to prevent and/or treat lymphedema. We have previously demonstrated that 9-cis retinoic acid (9-cis RA) can promote lymphangiogenesis in vitro and can limit lymphedema in vivo. The specific aims of this proposal are: 1) To elucidate the mechanism by which 9-cis RA acts to minimize surgically induced lymphedema in vivo; 2) To determine the minimal effective dose (MED) of 9-cis RA necessary to prevent post- surgical lymphedema; and 3) To determine effect of 9-cis RA on vascularized lymph node flap transfers (VLN) using a novel transgenic fluorescent lymphatic reporter rat. We expect data from these studies to support rapid translation to human clinical trials, especially since 9-cis RA (Alitretinoin) is already FDA approved. Data from this proposal has the potential to re-purpose 9-cis RA as the first pharmacologic agent used to significantly impact the onset and progression of secondary lymphedema. Dr. Alex Wong, the principal investigator of this grant, is a surgeon-scientist who has a long-term goal of becoming an independent investigator in the field of lymphedema. He goal is to become an expert in RA therapy for lymphedema and lead clinical trials using RA and other modalities. Dr. Young-Kwon Hong, PhD is the primary mentor for this grant, is an international expert in lymphagiogenesis and lymphedema. He is an established investigator with NIH R-series funding and has a solid track record in mentoring PhD and MD scientists to independence. The proposed career development plan that integrates scientific investigation, formal course work, and frequent meetings to assess scientific progression will be essential for Dr. Wong's goals towards independence.

项目概要/摘要 淋巴水肿是一种无法治愈的疾病，其特征是淋巴损伤后组织肿胀。它影响超过 全球有 1.4 亿人因四肢残疾而生活质量低下， 毁容以及复发性肢体威胁感染的风险。在美国，淋巴水肿通常是由于淋巴 淋巴结切除术与乳腺癌或盆腔肿瘤等恶性肿瘤的治疗相关。有 目前尚无已知的药物疗法可以预防或逆转淋巴水肿的临床进展 人类。然而，最近的数据表明，手术转移血管化淋巴结（VLN）以取代 受损的淋巴结或转移远端肢体的淋巴流可能会限制甚至逆转疾病 进展。由于淋巴损伤和回流是淋巴水肿的根本原因，我们假设 在淋巴管损伤开始时外源性刺激淋巴管生成可能是一种有效的治疗方法。 预防和/或治疗淋巴水肿的策略。我们之前已经证明9-顺式视黄酸（9-cis RA）可以在体外促进淋巴管生成，并且可以在体内限制淋巴水肿。本次活动的具体目标 建议是： 1) 阐明 9-cis RA 的作用机制，以尽量减少手术引起的 体内淋巴水肿； 2) 确定预防后遗症所需的 9-cis RA 的最小有效剂量 (MED) 手术淋巴水肿； 3) 确定 9-cis RA 对血管化淋巴结瓣转移 (VLN) 的影响 使用新型转基因荧光淋巴报告鼠。我们期望这些研究的数据能够支持 快速转化为人体临床试验，特别是因为 9-cis RA（阿利维A酸）已获得 FDA 批准。数据 根据该提案，有可能将 9-cis RA 重新用作第一种用于治疗的药物 显着影响继发性淋巴水肿的发生和进展。校长 Alex Wong 博士 这项资助的调查员是一位外科医生科学家，他的长期目标是成为独立的 淋巴水肿领域的研究者。他的目标是成为 RA 淋巴水肿治疗专家 领导使用 RA 和其他方式的临床试验。 Young-Kwon Hong 博士是该项目的主要导师 Grant 是淋巴管生成和淋巴水肿方面的国际专家。他是一名资深调查员 NIH R 系列资助，并在指导博士和医学博士科学家独立方面拥有良好的记录。这 提出的职业发展计划，整合了科学研究、正式课程工作和频繁的 评估科学进展的会议对于黄博士实现独立的目标至关重要。