BLRD Research Career Scientist Award Application

项目摘要/摘要：黄颜芬博士是一名研究生物医学工程师，他 翻译研究项目的重点是心血管疾病和创伤性肌肉损伤，这两种疾病 在退伍军人群体中具有很高的相关性。她的研究计划的总体目标是开发小说 改善心血管和骨骼组织再生和功能恢复的治疗策略 退伍军人所经历的肌肉疾病/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。她实验室研究计划的主要重点领域是 研究细胞外基质中的生化和生物力学信号在调节细胞命运和 组织功能，以便将基本见解转化为新的治疗方法，促进心血管和 退伍军人的骨骼肌再生。她的活跃的VA BLR&D功勋奖专注于治疗 创伤性肌肉损伤使用工程骨骼肌，更好地模拟生理组织和 天然骨骼肌的血管化。特别是，她使用了平行排列的纳米纤维胶原蛋白 引导新形成的肌肉纤维的组织和同步收缩的支架。另外， 骨骼肌祖细胞和血管内皮细胞之间的细胞间相互作用 移植后可进行吻合的带血管的肌肉组织。她的实验室报告说 在治疗前内皮化和平行排列工程骨骼肌方面的知识诱导更多 新生肌肉再生、有组织的肌纤维结构和灌流的血管系统，比工程化的 肌肉缺乏前内皮化或空间图案。蛋白质组学和转录组分析揭示了新的 对调节这一过程的基本信号通路和细胞因子分布的洞察。在并行战略中 为了增强肌肉再生，她还开发了现成的支架，可以控制肌肉的释放 可移植到VML部位的修复因子，结合再生性康复。使用 资金来自活跃的VA RR&D功勋奖，她将康复锻炼与心脏移植相结合 定向纳米纤维支架，释放促肌生成因子，促进血管形成，神经肌肉 结合点的形成和力的产生。这些研究结果影响了容积肌的治疗 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而造成的损失。 除骨骼肌外，另一个研究重点领域是应用药物治疗周围动脉疾病 诱导血运重建的策略。在一项有效的NIH R01拨款中，她证明了空间上对齐的 纳米纤维胶原支架作为有效载体增强细胞的促存活和促血管生成 移植的治疗细胞的功能，导致小鼠模型的血液灌流恢复 外周动脉疾病。从定向纳米纤维胶原的促存活作用中获得的见解 支架现在已经申请了专利。在一个平行的策略中，她开发了具有可调节的蛋白质模拟水凝胶 注射僵硬提高人诱导多能干细胞来源内皮细胞的存活率 患有外周动脉疾病的小鼠。她证明了脑缺血后内皮细胞的存活 外周动脉疾病小鼠的肢体在蛋白水凝胶内给药时显著高于 在生理盐水中。此外，该水凝胶还促进诱导的多能干细胞来源的内皮细胞分泌 血管生成旁分泌因子，有助于形成更多的微血管。这项工作现在正在进行 在另一个活跃的NIH R01拨款中进一步发展，以研究应力松弛力学性能的作用 水凝胶在调节内皮细胞存活和血运重建中的作用。总而言之，在过去10年中， 在退伍军人医学中心工作期间，她发表了75篇同行评议的出版物和专利。她有很强的责任感 为当地和全国退伍军人管理局服务，培训退伍军人管理局学员，并与退伍军人管理局及其附属公司合作研究 调查人员。

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.