Uncovering Regeneration-Permissive Cues in Lower Vertebrate Retina to Inform Retinal Regenerative Medicine

1606128 Carrier，Rebecca L. 视网膜变性，特别是与衰老相关的视网膜变性，是一种普遍且日益严重的健康问题，目前影响着美国210万人，并给经济带来了巨大负担（每年约20亿美元）。它是全球失明的主要原因。细胞移植策略已经显示出巨大的前景，但受到细胞存活和整合水平低（1%）的显著限制。拟议的研究旨在阐明使移植细胞存活和整合所需的化学和物理线索。这种基本的定量理解将提供一个框架，以指导未来的视网膜再生策略和材料设计，以作为有效的细胞递送载体。拟议的项目还将培育一个有凝聚力的教育计划，包括从K-12到研究生的各个教育级别的教学。虽然一些低等脊椎动物的视网膜可以再生，但人类的视网膜却不能。低等脊椎动物基质组成、结构和机械性质在组织再生中的作用尚未被探索，但可能是重要的，并且可以被利用来实现再生医学的重大进展。PI最近的初步结果表明，哺乳动物视网膜祖细胞显示出惊人的不同行为时，引入到较低的脊椎动物（美西螈）视网膜，以类似于细胞移植的方式，相对于哺乳动物视网膜。具体地，在较低脊椎动物视网膜中的RPC表现出显著增强的细胞存活和整合到视网膜中-对再生至关重要的过程。该项目将分析与成年哺乳动物视网膜相比，低等脊椎动物再生允许视网膜微环境的化学和物理特征。该研究将包括深入研究人类视网膜祖细胞对下脊椎动物视网膜基质的反应，包括附着，存活，分化和3D迁移，这些过程对成功的细胞移植策略至关重要。该研究将分析在存在和不存在组织条件培养基的情况下，细胞对完整组织和脱细胞基质的反应，以解析细胞与非细胞（基质）组分以及可溶性与不溶性线索的影响。重要的是，一个综合的系统生物学方法将定量相关的组织/基质/可溶性因子线索和细胞信号事件的细胞反应。这一定量机制的理解将提供一个框架，以指导未来的视网膜再生策略和生物材料design.This由CBET部门的生物技术和生物化学工程计划的奖项是由材料研究部门的生物材料计划共同资助。

1606128 Carrier, Rebecca L. Retinal degeneration, particularly associated with aging, is a widespread and increasing health problem currently affecting 2.1 million people in the U.S. and imposing a substantial burden on the economy (~$2 billion annually). It is the leading cause of blindness worldwide. Cell transplantation strategies have shown tremendous promise, but are significantly limited by low levels of cell survival and integration (1%). The proposed studies aim to elucidate the chemical and physical cues required to enable survival and integration of transplanted cells. This fundamental, quantitative understanding will provide a framework to guide future retinal regeneration strategies and design of materials to serve as effective cell delivery vehicles. The proposed project will also nurture a cohesive education plan including teaching and learning across education levels spanning from K-12 to postgraduate. While the retinas of some lower vertebrate species do regenerate, the human retina does not. The role of lower vertebrate matrix composition, structure, and mechanical properties in tissue regeneration has not been explored, yet is likely significant and could be exploited to enable significant advances in regenerative medicine. The PI's recent preliminary results indicate that mammalian retinal progenitor cells display strikingly different behavior when introduced to the lower vertebrate (axolotl) retina, in a manner analogous to cell transplantation, relative to a mammalian retina. Specifically, the RPCs in the lower vertebrate retina exhibit markedly enhanced cell survival and integration into the retina - processes central to regeneration. This project will analyze the chemical and physical features of the lower vertebrate regeneration-permissive retinal microenvironment compared to that of adult mammalian retina. The research will include an in-depth study of human retinal progenitor cell response to lower vertebrate retinal matrix, including attachment, survival, differentiation and 3D migration, processes essential to successful cell transplantation strategies. The study will analyze cell response to both intact tissue and decellularized matrix, in the presence and absence of tissue-conditioned medium, to parse effects of cellular vs. acellular (matrix) components and soluble vs. insoluble cues. Importantly, an integrated systems-biology approach will quantitatively relate cell response to tissue/matrix/soluble factor cues and cell signaling events. This quantitative mechanistic understanding will provide a framework to guide future retinal regeneration strategies and biomaterial design.This award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research.