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.

项目摘要/摘要 淋巴水肿是一种不治之症，其特征是淋巴损伤后组织肿胀。它会影响到 全世界有1.4亿人，与肢体残疾导致的生活质量低下有关， 毁容，以及复发的威胁肢体的感染的风险。在美国，淋巴水肿通常是由于淋巴引起的 与乳腺癌或骨盆肿瘤等恶性肿瘤的治疗相关的结节切除。确实有 目前还没有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，外科手术转移的血管蒂淋巴(VLN)取代 受损的淋巴结或从远端肢体分流的淋巴可能会限制甚至逆转疾病。 进步。由于淋巴损伤和返流是淋巴水肿的根本原因，我们假设 在开始淋巴管损伤时外源性刺激淋巴管生成可能是有效的 预防和/或治疗淋巴水肿的策略。我们先前已经证明了9-顺式维甲酸(9-顺式维甲酸 RA)在体外可促进淋巴管生成，在体内可抑制淋巴水肿。这样做的具体目的是 建议如下：1)阐明9-顺式维甲酸减少手术诱导的作用机制。 2)确定9-顺式维甲酸预防淋巴水肿所需的最小有效剂量(MED)。 外科淋巴水肿；3)确定9-顺式维甲酸对吻合血管的淋巴组织瓣转移的影响。 使用一种新的转基因荧光淋巴管报告大鼠。我们预计这些研究的数据将支持 快速转化为人体临床试验，特别是因为9-顺式维甲酸(阿立维甲素)已经获得FDA批准。数据 这项提案有可能将9-顺式维甲酸重新用作第一种用于 显著影响继发性淋巴水肿的发生和发展。校长亚历克斯·黄博士 这笔赠款的研究人员是一名外科医生兼科学家，他的长期目标是成为一名独立的 淋巴水肿领域的研究人员。他的目标是成为治疗淋巴水肿和类风湿关节炎的专家 使用RA和其他方式领导临床试验。洪英权博士是这项研究的主要导师 格兰特是淋巴生成和淋巴水肿方面的国际专家。他是一名知名的调查员， NIH R系列资助，在指导博士和MD科学家走向独立方面有着坚实的记录。这个 建议的职业发展计划，将科学调查、正规课程工作和经常 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。