Novel Mechanisms in the Resolution of Post-Surgical Lymphedema

解决术后淋巴水肿的新机制

• 批准号: 10580412
• 负责人: Aladdin Hasan Hassanein
• 金额: $ 14.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580412
• 关键词: Adipose tissue; Adopted; Affect; American; Animal Model; Area; Award; Axilla; Breast Cancer Patient; Breast Melanoma; Bypass; C-Type Lectins; Cancer Survivor; Chronic; Circulation; Clinical; Clinical Research; Consumption; Dedications; Deformity; Deposition; Development; Disease; Down-Regulation; Equipment; Excision; Exhibits; Fibrosis; Foundations; Funding; Gene Delivery; Gene Transfer; Genes; Genetic; Goals; Grant; Human; Iatrogenesis; Indiana; Infection; Injury; Institution; Intercellular Fluid; Junior Physician; Laboratories; Lead; Limb structure; Liquid substance; Lymph; Lymph Node Dissections; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic function; Lymphedema; Malignant Neoplasms; Master of Science; Mentors; Mentorship; Microsurgery; Modeling; Morbidity - disease rate; Mus; Nanotechnology; Oncology; Operative Surgical Procedures; PLCG2 gene; Pain; Pathway interactions; Patients; Persons; Physical therapy; Physicians; Physiological; Plasmids; Postoperative Period; Procedures; Process; Research; Research Personnel; Resolution; Scientist; Secondary to; Shunt Device; Signaling Molecule; Site; Surgical Management; Swelling; Tail; Technology; Testing; Time; Tissues; Topical application; Training; Translational Research; Universities; Vascularization; Veins; Venous; Venous system; Viral Vector; Virus; Work; arm; career development; clinical application; electric field; experience; experimental study; iatrogenic injury; improved; in vivo; injured; innovation; insight; lymph nodes; lymphatic dysfunction; lymphatic vessel; malignant breast neoplasm; medical schools; mouse model; nanochannel; nanotransfection; novel; novel strategies; operation; physical therapist; professor; programs; receptor; recurrent infection; vector

Project Summary This is a mentored clinical scientist research career development proposal for a junior physician who clinically treats post-surgical lymphedema and is training to become an independent investigator. Lymphedema results from lymphatic dysfunction and is characterized by limb enlargement. It is most commonly caused by iatrogenic injury to the lymphatic system secondary to lymph node excision during the surgical management of cancer (e.g, breast cancer and melanoma). It is estimated that 5-10 million Americans have lymphedema and 250 million people are affected worldwide. Morbidity from this chronic condition includes frequent infection, pain, and altered function. There is currently no cure for this disease. Management includes compression, excisional procedures, and microsurgical operations vascularized lymph node transfer and lymphovenous bypass (LVB). During LVB, lymphatics in the affected extremity are anastomosed to veins to bypass the injured area. The operation is technically challenging, time consuming, and requires advanced equipment. One-third of patients develop lymphedema following lymphadenectomy. The two thirds of those patients that do not develop lymphedema have transient postoperative limb swelling which resolves spontaneously. Similarly, a mouse tail model of lymphedema spontaneously resolves the swelling. We propose the novel hypothesis that lymphedema-induced spontaneous lymphovenous shunts and lymphangiogenesis lead to the physiological resolution of lymphedema. We use a murine tail model of lymphedema to test our hypothesis. In Aim 1, we will determine the mechanism responsible for spontaneous resolution of lymphedema. In addition, this proposal presents an innovative approach using tissue nanotransfection technology (TNT) to induce lymphovenous shunts and lymphangiogenesis to improve lymphedema. In Aim 2, we hypothesize that TNT can be used to topically, focally deliver genetic cargo to improve lymphedema by targeting the C-type lectin like receptor (CLEC- 2), Syk, and Slp76 pathways which keep lymphatics separated from veins. Inducing lymphovenous shunts would act similarly to LVB currently performed clinically to treat lymphedema. In summary, these experiments will be high impact in identifying the mechanism of spontaneous lymphatic resolution. The proposed work adopts a novel approach to managing lymphedema using focal, non-global TNT directly at the affected area. The candidate is an Assistant Professor at Indiana University who is dedicated to becoming a physician-scientist. He has obtained a previous Master’s degree in translational and clinical research at Harvard Medical School. The candidate has multiple pilot and foundation grants, a startup research package, dedicated laboratory space, and 40% protected time which will be increased to 75% upon obtaining the K08 grant. There is an expert mentorship panel, including the Vice-Chair of Surgery and the candidate’s Division Chief, who are well funded and experienced in mentoring physician scientists. There is strong institutional commitment which will facilitate the candidate transition to an independent investigator.

项目摘要 这是一个指导临床科学家的研究职业发展建议的初级医生谁临床 治疗术后水肿，并正在接受培训，成为一名独立的调查员。淋巴水肿结果 淋巴功能障碍，其特征是肢体肿大。最常见的原因是医源性 在癌症的外科处理过程中继发于淋巴结切除的淋巴系统损伤（例如， 乳腺癌和黑色素瘤）。据估计，美国有5- 1000万人患有淋巴水肿，2.5亿人患有淋巴水肿 全世界的人都受到影响。这种慢性病的发病包括频繁感染、疼痛和改变。 功能目前还没有治愈这种疾病的方法。管理包括压迫，切除程序， 显微外科手术包括带血管蒂淋巴结转移和淋巴静脉转流术。直播时， 患肢的血管与静脉相连，绕过受伤部位。操作 技术上具有挑战性，耗时，需要先进的设备。 三分之一的患者在淋巴结切除术后出现水肿。三分之二的病人 未出现一过性术后肢体肿胀，可自行消退。类似地第 小鼠尾部水肿模型自发地消除肿胀。我们提出了一个新的假设， 水肿诱导的自发性淋巴静脉分流和淋巴管生成导致生理性 水肿消退。我们使用鼠尾模型的水肿来测试我们的假设。在目标1中，我们 确定水肿自发消退的机制。此外，该提案 提出了一种使用组织纳米转染技术（TNT）诱导淋巴静脉的创新方法 分流和淋巴管生成以改善水肿。在目标2中，我们假设TNT可用于 通过靶向C型凝集素样受体（CLEC-），局部、局部递送遗传货物以改善水肿。 2）、Syk和Slp 76通路，其保持动脉与静脉分离。诱导淋巴静脉分流 作用类似于目前临床上用于治疗水肿的LVB。 综上所述，这些实验将在确定自发性淋巴结转移的机制方面具有重要意义。 分辨率拟议的工作采用了一种新的方法来管理水肿使用焦点，非全球TNT 直接在受影响的地区。候选人是印第安纳州大学的助理教授，致力于 成为一名物理学家兼科学家。他曾获得转化和临床研究硕士学位 在哈佛医学院。候选人有多个试点和基金会赠款，启动研究包， 专用实验室空间，40%的保护时间，在获得K 08后将增加到75% 格兰特.有一个专家指导小组，包括外科副主席和候选人的部门 主任，谁是资金充足，并在指导医生科学家的经验。有强大的制度 这将有助于候选人过渡到独立调查员。