A Therapeutic Tool for ULtrasound-Guided Stem Cell Therapy

描述(申请人提供)：在美国，缺血性心脏病是主要的死亡原因，干细胞疗法可以使受损心脏组织的射血分数提高10%以上。不幸的是，许多干细胞在植入几天后存活下来，通常位于缺氧或纤维化的组织中，不能接受组织再生-我的近亲 长期目标是提高心脏干细胞治疗的疗效。令人兴奋的初步数据表明，二氧化硅纳米颗粒可以用于研究干细胞，并确保它们在移植后存活。这些纳米粒子具有超声对比度，可以在图像引导下传递远离纤维化的物质，而不是现有的仅在注射后才进行成像的范例。该多功能纳米颗粒还具有高分辨率随访的MRI对比度。最后，相同的纳米颗粒提供持续的生长因子释放，以促进细胞增殖。这种纳米颗粒是促进我通过干细胞疗法改善心脏功能的长期目标的理想载体，但这种方法需要在这里提出的额外改进和验证。该工作流程分为三个主要部分来验证我的假设，即将存活剂的缓释载体与实时显像剂相结合，可以克服细胞输送和细胞存活率差的挑战。1)我将用材料化学来改善纳米颗粒的生物降解性和孔隙率(用于负载存活剂)。然后，这种纳米颗粒将通过细胞和动物毒性研究进行评估，并在需要时进行提炼。2)存活剂将被装载到纳米颗粒中，并用于在具有挑战性的体外生长条件下治疗干细胞。这些药物将进行迭代优化，以改善治疗。3)最后，我将使用缺血性疾病的动物模型和成像来确定纳米颗粒启用的干细胞治疗的疗效。创新之处在于实时、定量成像，它允许过渡到心脏内注射而不是冠脉内注射，从而植入心脏最容易接受的组织。海绵状纳米颗粒的持续释放将与困扰这一领域的细胞死亡作斗争。这项提议为干细胞治疗提供了一种全新的工具和方法，其应用范围将远远超出心血管医学。最后，这笔助学金促进的研究和专业培训是我在斯坦福大学教授的指导和指导下实现独立职业生涯目标的理想垫脚石。Sanjiv Sam Gambhir和Joseph Wu--国际知名的细胞成像和心血管研究专家。

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of death in the U.S.A., and stem cell therapy can improve the ejection fraction of damaged cardiac tissue by over 10%. Unfortunately, many stem cells days after implantation and those that do survive are often located in hypoxic or fibrotic tissue that are unreceptive to tissue regeneration-my near term goal is to improve the efficacy of cardiac stem cells therapy. Exciting preliminary data suggests that silica nanoparticles can be used to both study stem cells and ensure their survival after transplant. These nanoparticles have ultrasound contrast for image-guided delivery away from fibrosis as opposed to the existing paradigm of imaging only after injection. The multifunctional nanoparticle also has MRI contrast for high resolution follow-up. Finally, the same nanoparticle offers sustained release of growth factors to encourage cell proliferation. This nanoparticle is the ideal vehicle to facilitate my long-term objective of improving heart function with stem cell therapy, but this approach requires the additional refinement and validation proposed here. The workflow is divided into three main components to test my hypothesis that combining a sustained release delivery vehicle for prosurvival agents with a real time imaging agent can overcome challenges with both cell delivery and poor cell survival. 1) I will improve the biodegradation and porosity (for loading prosurvival agents) of the nanoparticle with materials chemistry. The nanoparticle will then be evaluated with cell and animal toxicity studies and refined if needed. 2) Prosurvival agents will be loaded into nanoparticles and used to treat stem cells under challenging growth conditions ex vivo. The agents will be iteratively optimized to improve therapy. 3) Finally, I will use animal models of ischemic disease and imaging to determine the efficacy of nanoparticle-enabled stem cell therapy. The innovation lies in real-time, quantitative imaging, which allows a transition to intra-cardiac injection rather tha intra-coronary delivery and thus implantation into the most receptive tissue in the heart. Sustained release of prosurvival agents from the sponge-like nanoparticle will combat the cell death that plagues this field. This proposal advances a fundamentally new tool and approach to stem cell therapy, which will have broad applications well beyond cardiovascular medicine. Finally, the research and professional training facilitated by this grant comprise an ideal stepping-stone to my career goal of an independent career with guidance and mentoring from Stanford Profs. Sanjiv Sam Gambhir and Joseph Wu-internationally renowned experts in cell imaging and cardiovascular research.