BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10703808
• 负责人: Ngan F. Huang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703808
• 关键词: Ablation; Adipose tissue; Anastomosis - action; Animals; Area; Award; Biochemical; Biocompatible Materials; Biomechanics; Biomedical Engineering; Biomedical Research; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Caring; Cell Fraction; Cell Survival; Cell secretion; Cells; Circulation; Cues; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Endothelial Cells; Endothelium; Engineering; Extracellular Matrix; Fostering; Funding; Generations; Geometry; Goals; Grant; Health; Human; Hydrogels; Hypertension; Incidence; Injections; Injury; Ischemia; Knowledge; Laboratories; Laboratory Research; Legal patent; Limb structure; Mechanics; Mediating; Medical center; Mus; Muscle; Muscle Fibers; Muscle satellite cell; Myocardial Infarction; Myopathy; Neuromuscular Junction; Nutrient; Obstruction; Oxygen; Pattern; Peer Review; Perfusion; Peripheral arterial disease; Physiological; Play; Process; Productivity; Proteins; Proteomics; Publications; Publishing; Quality of life; Rehabilitation therapy; Relaxation; Reporting; Research; Research Personnel; Risk Factors; Role; Saline; Scientist; Seminal; Services; Signal Pathway; Site; Skeletal Muscle; Smoking; Source; Stress; Structure; Therapeutic; Tissue Engineering; Tissue Survival; Tissue Transplantation; Tissues; Training; Translating; Transplantation; United States Department of Veterans Affairs; United States National Institutes of Health; Vascular Endothelial Cell; Vascularization; Veterans; Work; angiogenesis; blood perfusion; career; collagen scaffold; controlled release; cytokine; exercise rehabilitation; experience; functional restoration; high risk; human old age (65+); improved; indexing; induced pluripotent stem cell; injured; insight; limb ischemia; mechanical properties; military veteran; mimetics; mortality; mouse model; muscle engineering; muscle form; muscle regeneration; muscular structure; nano; nanofibrillar; novel therapeutic intervention; novel therapeutics; paracrine; programs; regenerative rehabilitation; restoration; scaffold; tissue regeneration; transcriptomics; translational research program; vascular tissue engineering; volumetric muscle loss

PROJECT SUMMARY / ABSTRACT: Dr. Ngan F. Huang, PhD is a Research Biomedical Engineer whose translational research program focuses on cardiovascular diseases and traumatic muscle injury, both of which are highly relevant in Veteran populations. The overall goal of her research program is to develop novel therapeutic strategies to improve tissue regeneration and functional restoration to cardiovascular and skeletal muscle diseases/injuries experienced by Veterans. These therapeutic strategies are aimed to reduce mortality and improve the quality of life of Veterans. The primary focus area of her laboratory's research program is to study the role of biochemical and biomechanical cues within the extracellular matrix in modulating cell fate and tissue function, in order to translate the basic insights into novel therapies that promote cardiovascular and skeletal muscle regeneration in Veterans. Her active VA BLR&D Merit award focuses on the treatment of traumatic muscle injury using engineered skeletal muscle that better mimics the physiological organization and vascularization of native skeletal muscle. In particular, she employs parallel-aligned nanofibrillar collagen scaffolds to guide the organization and synchronized contractility of newly formed muscle fibers. Additionally, inter-cellular interactions between skeletal muscle progenitor cells and vascular endothelial cells create a vascularized muscle tissue that can undergo anastomosis upon transplantation. Her laboratory reports seminal knowledge in that treatment of pre-endothelialized and parallel-aligned engineered skeletal muscle induces more de novo muscle regeneration, organized myofiber structure, and perfused vasculature, than in engineered muscle lacking pre-endothelization or spatial patterning. Proteomic and transcriptomic analysis reveal new insights into the basic signaling pathways and cytokine profile that mediate this process. In a parallel strategy to augment muscle regeneration, she also developed off-the-shelf scaffolds with controlled release of muscle reparative factors that can be transplanted to the site of VML in conjunction with regenerative rehabilitation. With funding from an active VA RR&D Merit award, she merges rehabilitative exercise with the transplantation of aligned nanofibrillar scaffolds that release pro-myogenic factors to improve vascularization, neuromuscular junction formation, and force generation. These research findings impact the treatment of volumetric muscle loss by synergizing therapeutic cells, instructive biomaterials, and rehabilitation to promote muscle regeneration. Besides skeletal muscle, another research focus area is the treatment of peripheral arterial disease using strategies to induce revascularization. In an active NIH R01 grant, she demonstrates that spatially aligned nanofibrillar collagen scaffolds serve as effective carriers to enhance the pro-survival and pro-angiogenic function of transplanted therapeutic cells, leading to the restoration of blood perfusion in murine models of peripheral arterial disease. The insights gained from the pro-survival effects of aligned nanofibrillar collagen scaffolds have now been patented. In a parallel strategy, she develops protein mimetic hydrogels with tunable stiffness to improve the survival of human induced pluripotent stem cell-derived endothelial cells upon injection mice animals with peripheral arterial disease. She demonstrates that endothelial survival within the ischemic limb of mice with peripheral arterial disease is significantly higher when delivered within the protein hydrogel than in saline. Moreover, the hydrogel promotes induced pluripotent stem cell-derived endothelial cell secretion of angiogenic paracrine factors, which contribute to the formation of more microvasculature. This work is now being further developed in another active NIH R01 grant to study the role of stress relaxation mechanical properties of hydrogels in modulating endothelial cell survival and revascularization. In summary, during the past 10 years at the VA Medical Center, she published 75 peer-reviewed publications and patents. She has a strong commitment to service to the local and national VA, training of VA mentees, and collaborative research with VA and affiliate investigators.

项目总结/摘要：Dr. Ngan F. Huang博士是一名研究生物医学工程师， 转化研究计划的重点是心血管疾病和创伤性肌肉损伤，两者都是 与退伍军人群体密切相关。她的研究计划的总体目标是开发新的 改善心血管和骨骼组织再生和功能恢复的治疗策略 退伍军人经历的肌肉疾病/损伤。这些治疗策略旨在降低死亡率 并提高退伍军人的生活质量。她的实验室的研究计划的主要重点领域是 研究细胞外基质中生物化学和生物力学线索在调节细胞命运中的作用， 组织功能，以便将基本见解转化为促进心血管和 退伍军人骨骼肌再生她积极的VA BLR&D优异奖侧重于治疗 使用更好地模拟生理组织的工程化骨骼肌的创伤性肌肉损伤， 天然骨骼肌的血管化。特别是，她采用平行排列的纳米纤维胶原蛋白 支架来引导新形成的肌肉纤维的组织和同步收缩。此外，本发明还 骨骼肌祖细胞和血管内皮细胞之间的细胞间相互作用产生了 血管化的肌肉组织可以在移植时进行吻合。她的实验室报告 在预内皮化和平行排列工程化骨骼肌的治疗中的知识诱导更多的 从头肌肉再生，有组织的肌纤维结构，和灌注的血管，比在工程 缺乏内皮化前或空间模式的肌肉。蛋白质组和转录组分析揭示了新的 深入了解介导这一过程的基本信号通路和细胞因子谱。在一个平行的战略中， 为了增强肌肉再生，她还开发了现成的支架， 可以移植到VML部位的修复因子与再生康复结合。与 从一个积极的VA RR&D优异奖的资金，她合并康复锻炼与移植， 释放促肌生成因子以改善血管形成、神经肌肉 结的形成和力的产生。这些研究结果影响了体积肌的治疗 通过协同治疗细胞、指导性生物材料和康复来促进肌肉再生。 除了骨骼肌，另一个研究重点领域是外周动脉疾病的治疗， 诱导血运重建的策略。在一项积极的NIH R 01资助中，她证明了空间对齐 纳米纤维胶原支架作为有效的载体， 移植的治疗性细胞的功能，导致血液灌注在小鼠模型中的恢复， 外周动脉疾病从排列的纳米原纤胶原蛋白的促生存作用中获得的见解 支架现已获得专利。在一个平行的策略中，她开发了蛋白质模拟水凝胶， 注射后改善人诱导多能干细胞衍生的内皮细胞存活的硬度 患有外周动脉疾病的小鼠。她证明了缺血性血管内内皮细胞的存活 当在蛋白质水凝胶内递送时，患有外周动脉疾病的小鼠的肢体的 在盐水中。此外，水凝胶促进诱导的多能干细胞衍生的内皮细胞分泌 血管生成旁分泌因子，其有助于形成更多的微血管。这项工作目前正在 在另一个积极的NIH R 01赠款进一步发展，以研究应力松弛的机械性能的作用， 水凝胶在调节内皮细胞存活和血管再生中的作用。总之，在过去10年中， 在VA医学中心，她发表了75篇同行评议的出版物和专利。她有很强的责任心 为当地和国家VA提供服务，培训VA学员，并与VA及其附属机构进行合作研究 investigators.