ENDOTHELIAL PROGENITOR CELLS FOR ENGINEERING VESSELS

描述（由申请人提供）：这项干细胞研究职业提升奖将使J. Koudy Williams博士能够重新指导他的研究，以干细胞方法预防和治疗血管疾病。拟议的研究计划将维克森林大学再生医学研究所（WFIRM）的干细胞/再生医学专业知识与Williams博士的血管生物学/外科专业知识相结合。Williams博士获得了该奖项的机构支持，并选择了Shay Soker博士作为他的赞助人。Shay Soker博士是WFIRM的核心科学家，其专长是在血管研究中使用干细胞/祖细胞。Williams博士选择了在血管外科（Geary博士）和生物力学（Berry博士）方面具有专业知识的共同研究人员，他们与Soker博士一起制定了职业发展计划，促进了他目前和未来在干细胞研究方面的工作。在美国，每年有超过50万例冠状动脉旁路移植术和5万例外周动脉旁路移植术，部分原因是动脉粥样硬化疾病的并发症。然而，高达30%需要动脉搭桥手术和其他血管手术的患者缺乏合适或足够数量的自体移植物材料。我们已经证明，内皮祖细胞（EPCs）在羊颈动脉间置移植中提供内皮并促进生物工程动脉通畅超过4个月。然而，目前尚不清楚epc种子生物工程血管在灵长类动物中的构建条件。灵长类动物在这项研究中的应用是至关重要的，因为它们在系统发育、血管疾病易感性和生理上与人类相似。我们的工作假设是，通过植入猴子内皮祖细胞的胶原支架制成的生物工程血管，然后自动用于制造动脉间位移植物，将适应生理流动条件，并在体内成熟，具有天然动脉的正常特性。为了解决这些问题，并验证这一假设，我们提出了以下具体目标：1)用从猴子骨髓中提取的内皮祖细胞作为胶原支架构建血管；2)研究生物工程血管移植物在非人灵长类动物体内的结构和功能特性。未来的研究方向将是将这种方法扩展到动脉粥样硬化的非人灵长类动物，并研究调节成熟的生物工程移植物重塑的机制。所提出的研究为需要冠状动脉搭桥手术、外周血管手术和其他血管疾病的患者开发血管提供了一个跳板。因此，这些研究是威廉姆斯博士与WFIRM同事合作的一个令人兴奋和独特的研究方向。

DESCRIPTION (provided by applicant): This Career Enhancement Award in Stem Cell Research will enable Dr. J. Koudy Williams to re-direct his research to stem cell approaches for the prevention and treatment of vascular disease. The proposed research plan combines the stem cell/regenerative medicine expertise of the Wake Forest University Institute of Regenerative Medicine (WFIRM) with the vascular biology/surgical expertise of Dr. Williams. Dr. Williams has institutional support for this award and has selected Dr. Shay Soker - a WFIRM core scientist whose expertise is the use of stem/progenitor cells in vascular research - as his sponsor. Dr. Williams has chosen co-investigators with expertise in vascular surgery (Dr. Geary), and biomechanics (Dr. Berry) who, with Dr. Soker, have devised a career development plan facilitating his current and future work in stem cell research. Over 500,000 coronary artery bypass grafts and 50,000 peripheral bypass grafts are performed annually in the United States due, in part, to complications of atherosclerotic disease. However, up to 30% of patients requiring arterial bypass surgery and other vascular procedures lack suitable or sufficient amounts of autologous graft material. We have shown that endothelial progenitor cells (EPCs) provide an endothelium and promote patency of bioengineered arteries for more than 4 months when used as carotid artery interposition grafts in sheep. However, the construction conditions of EPC-seeded bioengineered blood vessels in primates are currently unknown. The utility of primates in this research is critical because of their close phylogenetic, vascular disease susceptibility, and physiologic similarities to those of human beings. Our working hypothesis is that bioengineered blood vessels made from collagen scaffolds seeded with monkey EPCs and then used autologously to create an interpositional arterial graft will adapt to physiological flow conditions and mature in vivo to assume normal properties of native arteries. To address these questions, and test this hypothesis, we propose the following specific aims: 1) To construct blood vessels from collagen scaffolds seeded with EPCs from the bone marrow of monkey; and then 2) To examine the structural and functional properties of bioengineered vascular grafts when placed in nonhuman primates. Future directions of this research will be to extend this methodology to atherosclerotic nonhuman primates and examine the mechanisms regulating remodeling of the maturing bioengineered grafts. The proposed studies represent a stepping stone to the development of blood vessels to be used by individuals needing coronary artery bypass surgery, peripheral vascular surgery, and other vascular disorders. As such, these studies are an exciting and unique direction of research for Dr. Williams in collaboration with his colleagues at WFIRM.