Novel Mechanisms in the Resolution of Post-Surgical Lymphedema

解决术后淋巴水肿的新机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要这是一项精神上的临床科学家研究职业发展计划，适用于临床上的初级物理学宝藏后手术后的淋巴水肿，正在训练成为独立研究者。淋巴水肿结果来自淋巴功能障碍，以肢体膨胀为特征。它最常见由医源性引起癌症手术治疗期间淋巴结切除症的淋巴系统损伤（例如，乳腺癌和黑色素瘤）。据估计，有5-100万美国人患有淋巴水肿和2.5亿人们在全球受到影响。这种慢性病的发病率包括经常感染，疼痛和改变功能。目前无法治愈这种疾病。管理包括压缩，移动程序，和微外科操作血管化淋巴结转移和淋巴旁路（LVB）。在LVB期间受影响的肢体中的淋巴管吻合到静脉以绕过受伤区域。操作是在技术上挑战，耗时，需要高级设备。三分之一的患者在淋巴水肿后出现淋巴水肿。这些患者中的三分之二不发育淋巴水肿具有瞬间术后肢体肿胀，可以自发解决。同样，淋巴水肿的小鼠尾部模型可以在肿胀上解决肿胀。我们提出了新的假设淋巴水肿诱导的自发淋巴管和淋巴管生成导致生理淋巴水肿的分辨率。我们使用淋巴水肿的鼠尾模型来检验我们的假设。在AIM 1中，我们将确定负责淋巴水肿的发音分辨率的机制。此外，此提案使用组织纳米转染技术（TNT）提出了一种创新的方法来诱导淋巴分流和淋巴管生成以改善淋巴水肿。在AIM 2中，我们假设TNT可以用来从局部使用，通过靶向C型杠杆（如接收器），局部提供遗传货物以改善淋巴水肿（clec-- 2），SYK和SLP76途径，使淋巴机与静脉分开。诱导淋巴分流会与当前在临床上进行淋巴水肿的LVB相似。总而言之，这些实验将在识别发起淋巴的机理方面具有很大的影响解决。拟议的工作采用了一种新颖的方法来使用焦点，非全球TNT管理淋巴水肿直接在患处。候选人是印第安纳大学的助理教授，致力于成为身体科学家。他已经获得了翻译和临床研究的硕士学位在哈佛医学院。候选人有多个飞行员和基金会赠款，这是一个创业研究包，专用的实验室空间和40％的保护时间，获得K08后将增加到75％授予。有一个专业的Mentalship小组，包括手术副主席和候选人部门酋长，在心理身体科学家方面拥有丰富的资金和经验丰富。有强大的机构将促进候选人过渡到独立调查员的承诺。