CAREER: Brain tissue regeneration after stroke

1055922，Zhang成人脑中的损伤或病理过程经常导致各种组织结构的破坏。在脑损伤部位及以外的持续性细胞功能障碍和神经再生能力差导致形成由坏死组织和/或充满液体的空腔组成的不规则形状的损伤，这些损伤与长期的神经损伤相关。迄今为止，在临床环境中没有有效的治疗方法可用于脑损伤。目前的治疗方法主要集中在抗炎和药理学药物的神经保护上，但未能明显改善死亡率和神经学结局，这可能是由于它们无法在病变部位重建正常脑组织。在最近尝试通过神经移植重新填充脑损伤部位中，由于持续的组织炎症和损伤内缺乏任何支持性组织结构和血管，观察到移植细胞的存活和功能性差。迫切需要改造性方法来功能性地再生跨病变的脑组织。PI的长期职业目标是开发新的基于生物材料的工程方法，以解决与干细胞用于人体组织再生的潜力和利用相关的生命科学问题，重点是脑组织再生。作为PI职业生涯的一个启动，这个CAREER项目旨在开发一种可注射的水凝胶输送系统，以操纵脑内驻留的内源性神经干细胞（NSCs）在脑损伤部位进行结构再生。中风，共享共同的病理后遗症和脑损伤的结果，将被用作该项目的模型。总体假设是，旨在内源性神经干细胞功能分化以重新填充脑中的中风病变区的干细胞工程策略将促进病变腔的神经重新填充，从而显著改善中风患者的神经学结果。提出了三个研究方向。目标1：确定神经干细胞在细胞培养中迁移的最佳条件。目标2：动员和位点特异性控制内源性神经干细胞迁移到脑卒中病变区。目标3：为了诱导招募的内源性神经干细胞分化为脑卒中区的功能性神经细胞，并促进神经细胞与宿主神经回路的功能整合。一个全面的教育计划与本CAREER提案的研究目标相结合。PI的教育活动包括：1）开发可在谷歌上搜索的在线辅导计划，涵盖生物医学研究各个领域的基础知识，为各级学生和世界各地的自学者提供随时随地的无限制访问; 2）扩大K-12外展的持续活动，继续强调少数民族学生，妇女，（3）为高中理科教师制定教师再培训计划，以便在他们自己的学校中实施生物医学教材;四、通过将具有不同背景的学生合并到多学科项目中，同时积极让学生参与，解决科学和工程的多样性问题。来自历史黑人学院和大学（HBCU）的研究;以及5）维持资金充足的毕业生和研究生指导计划并促进他们的职业发展。 智力优点：这项拟议中的研究将通过填补差距来推进科学，该差距是基于体内组织工程的概念，使用患者自己的脑驻留干细胞来修复受损脑组织的结构。在这个项目中建立的基本范式将指导未来的努力，在各种组织的功能性再生的组织工程。克莱姆森大学-南卡罗来纳州医科大学联合生物工程项目提供了一个智力多学科的环境，促进跨学科的合作和指导，以确保PI的成功。 更广泛的影响：该研究将对生物材料、组织工程、干细胞生物学和工程、神经科学和再生医学等多个科学和技术领域产生重大影响。PI将研究与教育相结合的努力将激发各级学生对科学的热情和热情，并为他们在科学和工程研究中的终身职业做好准备。强调鼓励代表性不足的人口、少数民族、妇女和残疾学生参与研究，将研究成果纳入课程并通过外联活动向公众传播，将增强生物医学研究队伍的多样性，造福社会。

1055922, ZhangA damaging or pathological process in adult brain often results in the disruption of various tissue structures. Persistent cell dysfunction and poor neural regenerative capabilities at the brain lesion site and beyond lead to the formation of irregular shaped lesions comprised of necrotic tissue and/or a fluid-filled cavity that are associated with prolonged neurological impairment. To date, no effective treatment is available for brain lesion in clinical settings. Current treatments, which have been focused on anti-inflammation and neuroprotection with pharmacological agents, have failed to produce clear improvements in the mortality and neurological outcome, perhaps due to their inability to structurally regenerate normal brain tissue at the lesion site. In recent attempts to repopulate the brain lesion site through neural transplantation, poor survival and functionality of the transplanted cells were observed due to the ongoing tissue inflammation and the lack of any supportive tissue structures and vasculatures within the lesion. There is a compelling need for transformative approaches to functionally regenerate brain tissue cross lesions. The PI's long-term career goal is to develop novel biomaterial-based engineering approaches to address life science questions related to the potential and utilization of stem cells for human tissue regeneration, with an emphasis on brain tissue regeneration. As a jump-start of PI's career, this CAREER project aims to develop an injectable hydrogel-based delivery system to manipulate brain-resident endogenous neural stem cells (NSCs) for structural regeneration at brain lesion site. Stroke, which shares the common pathologic sequelae and outcome of brain lesions, will be used as the model in the project. The overall hypothesis is that a stem cell engineering strategy aiming at functional differentiation of endogenous neural stem cells to repopulate the stroke lesion zone in the brain would promote neural repopulation of the lesion cavity, leading to significant improvement in neurological outcome in stroke patients. Three research thrusts are proposed. Goal 1: To determine the optimal conditions for neural stem cell migration in cell culture. Goal 2: To mobilize and site-specifically control endogenous neural stem cells to migrate to the brain stroke lesion zone. Goal 3: To induce the differentiation of the recruited endogenous neural stem cells into functional neural cells in the stroke zone, and promote the functional integration of the neural cells with the host neural circuitry.A comprehensive educational plan is integrated with the research goals of this CAREER proposal. The PI's educational activities include: 1) development of google-searchable online tutoring programs that cover fundamentals in diverse areas of biomedical research to provide unlimited access from anywhere at anytime by students at all levels and world-wide self-learners; 2) expanding ongoing activities in K-12 outreach with continuing emphasis on the participation and retention of minority students, women, and students with disabilities into science and engineering research and educational programs; 3) establishing a teacher retraining program for high school science teachers to implement the biomedical educational materials in their own schools; 4) addressing diversity in science and engineering by merging students with diverse backgrounds in multidisciplinary projects while actively involving students from Historically Black Colleges and Universities (HBCUs) in research; and 5) maintaining a well-funded graduate and post-graduate mentoring program and fostering their career development. Intellectual merits: The proposed research will advance science by filling the gap for structural repair of damaged brain tissue based upon an in vivo tissue engineering concept using the patient's own brain-resident stem cells. Fundamental paradigms established in this project will direct future efforts for tissue engineering in a variety of tissues for functional regeneration. The Clemson University-Medical University of South Carolina joint bioengineering program provides an intellectual multidisciplinary environment that fosters interdisciplinary collaborations and mentoring to ensure PI's success. Broader impact: The research will generate great impact on several scientific and technological communities, including biomaterials, tissue engineering, stem cell biology and engineering, neuroscience, and regenerative medicine. PI's efforts in integrating research with education would motivate students at all levels for the passion and enthusiasm for science, and prepare them for life-long careers in science and engineering research. Emphasis on encouraging the participation of underrepresented populations, minorities, women, and students with disabilities in research, incorporating research findings into coursework and their dissemination to the public through outreach activities would enhance the diversity in the biomedical research workforce and benefit society.