CAREER: Brain tissue regeneration after stroke

[55][922]成人大脑的损伤或病理过程往往导致各种组织结构的破坏。脑损伤部位及其他部位持续的细胞功能障碍和较差的神经再生能力导致由坏死组织和/或充满液体的腔组成的不规则形状病变的形成，这与长期的神经损伤有关。到目前为止，临床上对脑损伤还没有有效的治疗方法。目前的治疗方法主要集中在抗炎和用药物保护神经方面，但在死亡率和神经预后方面并没有明显的改善，这可能是由于它们无法在病变部位结构上再生正常脑组织。在最近通过神经移植重新填充脑损伤部位的尝试中，由于持续的组织炎症和病变内缺乏任何支持性组织结构和血管系统，观察到移植细胞的存活率和功能较差。有一个迫切需要转化的方法来功能再生脑组织交叉病变。PI的长期职业目标是开发新的基于生物材料的工程方法，以解决与干细胞在人类组织再生中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职业生涯的开端，该career项目旨在开发一种可注射的基于水凝胶的递送系统，以操纵脑内内源性神经干细胞（NSCs）在脑损伤部位进行结构再生。脑卒中具有常见的病理后遗症和脑损伤的结局，将作为本项目的模型。总体假设是，干细胞工程策略旨在内源性神经干细胞的功能分化，以重新填充脑卒中损伤区，从而促进损伤腔的神经再生，从而显著改善卒中患者的神经预后。提出了三个研究重点。目的1：确定细胞培养中神经干细胞迁移的最佳条件。目标2：动员和定位特异性控制内源性神经干细胞迁移到脑卒中病变区。目的3：诱导募集的内源性神经干细胞向卒中区功能性神经细胞分化，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职业计划书的研究目标相结合。PI的教育活动包括：1)开发可谷歌搜索的在线辅导项目，涵盖生物医学研究的各个领域的基础知识，为所有水平的学生和世界各地的自学者提供随时随地的无限制访问；2)扩大正在进行的K-12外展活动，继续强调少数民族学生，妇女和残疾学生参与和保留科学和工程研究和教育计划；3)建立高中理科教师在本学校实施生物医学教材的教师再培训计划；4)通过在多学科项目中融合不同背景的学生，同时积极让传统黑人学院和大学（HBCUs）的学生参与研究，解决科学和工程领域的多样性问题；5)维持一个资金充足的研究生和研究生指导计划，促进他们的职业发展。智力优势：该研究将通过利用患者自身的脑驻留干细胞来填补基于体内组织工程概念的受损脑组织结构修复的空白，从而推进科学发展。本项目建立的基本范式将指导未来各种组织功能再生的组织工程工作。克莱姆森大学-南卡罗来纳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：该研究将对几个科学技术领域产生重大影响，包括生物材料、组织工程、干细胞生物学和工程、神经科学和再生医学。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，并为他们终身从事科学和工程研究做好准备。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人员的多样性，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.