Mesenchymal Stem Cell Application for Ischemic wound Healing

描述（由申请人提供）：Susan Volk博士曾在NIH赞助的VMD-PhD项目中接受过基础科学培训，随后作为兽医完成了专科临床培训。该提案涉及她的一个新的研究方向，专注于基于间充质干细胞（MSC）的慢性皮肤伤口治疗和伤口愈合的分子机制。导师Alan Flake博士将贡献干细胞治疗领域的专业知识，并指导候选人制定独立的研究计划。其他贡献者将提供伤口愈合，皮肤病理学和细胞外基质生物学领域的专业知识。学术部分将包括研讨会、研究伦理培训和研究生课程。候选人作为小动物软组织外科医生的有限临床活动将补充她的基础科学研究。研究将集中在建立局部应用MSC治疗缺血性伤口的潜在疗效和解剖其治疗作用的机制。缺血性伤口带来了巨大的临床挑战，住院时间延长，医疗费用高昂。迄今为止，缺血性溃疡和其他慢性不愈合伤口缺乏有效的治疗方法。该提案中的证据表明，骨髓来源的MSC改善缺血性伤口的愈合。待检验的假设是MSC通过直接和间接机制改善缺血性伤口愈合。Aim 1将评估MSC通过促进收缩、上皮形成和肉芽组织形成显著提高缺血性伤口愈合率的能力。这将使用两种缺血性伤口愈合模型完成：一种已建立的兔耳模型和一种将表征的鼠模型。目的2将检验MSC作为肌成纤维细胞直接促进伤口愈合和通过产生促进血管生成和上皮形成的旁分泌因子间接促进伤口愈合的假设。预计这些研究可能导致用于治疗缺血性伤口的组织工程方法;使用离体扩增的MSC，并且还提供对愈合缺血性组织至关重要的分子机制的实质性新见解。这种培训和研究的结合将使候选人能够过渡到一个完全独立的研究调查员，为软组织修复领域做出贡献，同时也保留了与临床兽医界的联系。

DESCRIPTION (provided by applicant): Dr. Susan Volk has previous basic science training in an NIH-sponsored VMD-PhD program and subsequently completed subspecialty clinical training as a veterinary surgeon. This proposal involves a new research direction for her, focusing on mesenchymal stem cell (MSC) based therapy for chronic cutaneous wounds and the molecular mechanisms of wound healing. The mentor, Dr. Alan Flake, will contribute expertise in the field of stem cell therapies and guide the candidate in developing an independent research program. Additional contributors will provide expertise in the fields of wound healing, dermatopathology and extracellular matrix biology. The academic component will include seminars, training in research ethics, and graduate-level courses. The candidate's limited clinical activities as a small animal soft tissue surgeon will complement her basic science investigation. Research will focus on establishing vulnerary efficacy of topically applied MSC to treat ischemic wounds and dissecting mechanisms of their therapeutic effects. Ischemic wounds create a formidable clinical challenge, with prolonged hospitalization and substantial healthcare expenditure. To date, effective therapies for ischemic ulcers and other chronic nonhealing wounds are lacking. Evidence in this proposal suggests that bone marrow derived MSC improve healing of ischemic wounds. The hypothesis to be tested is that MSC improve ischemic wound healing by both direct and indirect mechanisms. Aim1 will evaluate the capacity of MSC to significantly improve the rate at which ischemic wounds heal by promoting contraction, epithelialization and granulation tissue formation. This will be accomplished using two models of ischemic wound healing: an established rabbit ear model and a murine model that will be characterized. Aim 2 will test the hypotheses that MSC contribute directly to the wound healing as a myofibroblast and indirectly by producing paracrine factors that promote angiogenesis and epithelialization. It is anticipated that these studies may lead to tissue engineering approaches for treating ischemic wounds; using ex vivo expanded MSC and also provide substantial new insights into molecular mechanisms that are critical for healing ischemic tissues. This combination of training and research will allow the candidate to transition to a fully independent research investigator making contributions to the field of soft-tissue repair, while also retaining ties to the clinical veterinary community.