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.

项目摘要/摘要：Ngan F. Huang 博士是一位研究生物医学工程师，其 转化研究计划重点关注心血管疾病和创伤性肌肉损伤，这两种疾病 与退伍军人群体高度相关。她的研究计划的总体目标是开发新颖的 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/受伤。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。她的实验室研究计划的主要重点领域是 研究细胞外基质内的生化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疾病的新疗法 退伍军人的骨骼肌再生。她活跃的 VA BLR&D 优异奖专注于治疗 使用更好地模仿生理组织的工程骨骼肌来治疗创伤性肌肉损伤 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 支架引导新形成的肌纤维的组织和同步收缩。此外， 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 移植后可进行吻合的血管化肌肉组织。她的实验室报告具有开创性 预内皮化和平行排列的工程骨骼肌的治疗会诱导更多的知识 与工程相比，从头开始的肌肉再生、有组织的肌纤维结构和灌注的脉管系统 缺乏预内皮化或空间模式的肌肉。蛋白质组学和转录组学分析揭示了新的 深入了解介导这一过程的基本信号传导途径和细胞因子谱。在并行策略中 为了增强肌肉再生，她还开发了可控制肌肉释放的现成支架 可以与再生康复一起移植到 VML 部位的修复因子。和 在 VA RR&D 优异奖的资助下，她将康复锻炼与移植相结合 对齐的纳米纤维支架可释放促肌原因子以改善血管化、神经肌肉 连接的形成和力的产生。这些研究结果影响体积肌肉的治疗 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来减少损失。 除了骨骼肌之外，另一个研究重点领域是利用肌肉治疗外周动脉疾病 诱导血运重建的策略。在一项活跃的 NIH R01 资助中，她证明了空间对齐 纳米纤维胶原支架作为有效载体增强促存活和促血管生成 移植的治疗细胞的功能，导致小鼠模型中血液灌注的恢复 外周动脉疾病。从对齐的纳米纤维胶原蛋白的促生存作用中获得的见解 脚手架现已获得专利。在一项并行策略中，她开发了具有可调性的模拟蛋白质水凝胶 注射后提高人诱导多能干细胞衍生内皮细胞存活率的硬度 患有外周动脉疾病的小鼠。她证明了缺血区域内的内皮细胞存活 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明显高于 在盐水中。此外，水凝胶促进诱导多能干细胞衍生的内皮细胞分泌 血管生成旁分泌因子，有助于形成更多微血管。这项工作现在正在 在另一项活跃的 NIH R01 资助中进一步发展，以研究应力松弛机械性能的作用 水凝胶调节内皮细胞存活和血运重建。总结起来，在过去的10年里 在 VA 医疗中心，她发表了 75 篇经过同行评审的出版物和专利。她有坚定的承诺 为地方和国家 VA 提供服务、培训 VA 学员以及与 VA 及其附属机构进行合作研究 调查人员。