Novel Strategies in Bladder Tissue Engineering: Stem Cells and Silk Biomaterials

项目总结/摘要 我的总体目标是在这个建议是解决目前的局限性，在手术选择膀胱 重建，同时发展我的专业能力，过渡到一个独立的调查员。我 我的职业目标是在一流的学术机构担任实验室主任， 通过创造基于干细胞的创新疗法， 用于泌尿系统组织重建我的主要研究培训目标将是获得新的技术 泌尿外科组织工程系统和人类多能干细胞生物学方面的技能。这将是 通过额外的基础课程和实验室协议的实际操作完成， 在提案的目标中详细说明的技术。职业发展机制将包括指导性的 研讨会和辅导指导，在赠款写作，学术工作面试，实验室管理， 手稿准备。一个顾问委员会将评估我的科学和职业生涯的完成情况 发展里程碑，并促进我过渡到一个独立的调查员。 膀胱的组织工程方法最近已经开发， 用自体平滑肌细胞（SMC）接种的3D支架。这些策略导致了部分 在短期临床试验中恢复器官功能。然而，这些构建体用于 完全的缺损修复可能受到常规生物材料载体的次优性质的限制 功能活性细胞来源的可用性。丝基生物材料提供了一种特殊的 这些特征非常适合于支持膀胱功能，因此可以 解决了与当前支架材料相关的局限性。多能干细胞群，如 胚胎干细胞（ESC）和/或诱导多能干细胞（iPS）可以满足以下需要： 能够产生器官和患者特异性SMC的替代细胞来源。为了解决 目前膀胱功能组织工程（FTE）的局限性，我们将挑战整体假设： 使用与原代或干细胞衍生的SMC接种的丝基生物材料的FTE模式将促进 平滑肌缺损的巩固和膀胱功能的恢复。研究的具体目标 目的1：确定与原代SMC一起接种的丝基生物材料用于膀胱的功效 平滑肌组织再生目的2：评估ESC和iPS衍生的SMC作为细胞的效用 功能性膀胱组织工程的来源。

PROJECT SUMMARY/ABSTRACT My overall goal in this proposal is to address the current limitations in surgical options for bladder reconstruction while developing my professional abilities to transition into an independent investigator. My professional objective is to have a position as a lab director in a superb academic institution that will allow me to continue to expand the frontiers of regenerative medicine by creating innovative stem cell-based therapies for urological tissue reconstruction. My primary research training objectives will be to acquire new technical skills in urological tissue engineered systems and human pluripotent stem cell biology. This will be accomplished through additional fundamental coursework and hands on instruction in laboratory protocols and techniques as detailed in the aims of the proposal. Career development mechanisms will include instructive seminars and mentored guidance in grant writing, academic job interviewing, laboratory management, and manuscript preparation. An advisory committee will evaluate the completion of both my scientific and career development milestones and facilitate my transition into an independent investigator. Tissue engineering approaches for the urinary bladder have recently been developed utilizing 3D scaffolds seeded with autologous smooth muscle cells (SMCs). These strategies have led to partial restoration of organ functionality in short-term clinical trials. However, the efficacy of these constructs for complete defect repair may be limited by the suboptimal properties of conventional biomaterial carriers and availability of functionally competent cell sources. Silk-based biomaterials provide an exceptional combination of physical characteristics that are well suited to support bladder function and therefore may address limitations associated with current scaffold materials. Pluripotent stem cell populations such as embryonic stem cells (ESCs) and/or induced pluripotent stem (iPS) cells may fulfill the need for alternative cell sources capable of generating organ and patient-specific SMCs. In order to address the current limitations in bladder functional tissue engineering (FTE), we will challenge the overall hypothesis that: FTE modalities using silk-based biomaterials seeded with primary or stem cell-derived SMCs will promote smooth muscle defect consolidation and restoration of bladder function. The specific aims of the study are: Aim 1: Determine the efficacy of silk-based biomaterials seeded with primary SMCs for bladder smooth muscle tissue regeneration. Aim 2: Evaluate the utility of ESC and iPS-derived SMCs as cell sources for functional bladder tissue engineering.