Modifying adipocyte and pre-adipocyte cell fate in fibroadipose tissue of secondary lymphedema

项目摘要 继发性水肿是一种病态，在美国影响超过500万患者。 患有这种疾病的患者会出现淋巴滞留，发展为不可逆的皮下 患肢纤维脂肪沉积。因此，患者经历慢性疼痛， 活动性和功能、开放性伤口以及整体生活质量降低。在目标1中，我将研究 刺激增强脂肪细胞分化的信号传导介质可以减少总体纤维脂肪 通过防止病理性干细胞群的增殖来减少沉积。在目标2中，我将研究如何 抑制促存活信号传导介质可影响脂肪细胞和前脂肪细胞存活。在这个过程中， 我试图了解这些细胞的特定亚群是否更容易发生凋亡。最后在 目的3，我寻求开发一种局部细胞疗法，其避免了治疗的全身不良反应， 改变细胞分化或存活。在这个过程中，我将开发出一种治疗方法， 分泌微小RNA，为新型细胞疗法铺平了道路。 职业发展奖对我作为一名医生科学家的成熟是必不可少的， 科学和临床领导者进行研究，这是由我的病人面临的挑战，严格的启发， 在其评价的潜在发病机制，这种情况下，并翻译在其考虑， 治疗策略。我得到了一组在干细胞和脂肪细胞生物学方面具有专业知识的导师的支持， 临床水肿管理，并在学术整形外科的领导。我也得到了一个团队的支持 在水肿生物学、细胞治疗和转化医学方面拥有专业知识的其他科学顾问。 该机构致力于我的成功，与保护时间的活动提出了这个奖项，实验室 空间，工资支持和实验室资金。在5年职业发展奖期间，我将在我的 以前的专业知识与监测干细胞的命运使用谱系追踪小鼠模型，并添加新的科学 专业知识，我的医疗设备与单细胞RNA测序和生物信息学分析。我将参与 讲习班和研讨会，以建立我的技术技能，并发展必要的实验室领导技能。 在我完成职业发展奖的第四个年头，我将提交我的第一个R01提交， 目的是进一步推进我在职业发展奖期间获得的发现。完成后 在5年奖学金期间，我将期望在脂肪细胞生物学、细胞 治疗，和水肿，并建立了我在谱系追踪和RNA测序方面的技术专长， 为我所在机构的科学环境做出了广泛的贡献。

PROJECT SUMMARY Secondary lymphedema is a morbid condition affecting over 5 million patients in the United States. Patients with this condition develop lymphatic retention, which progresses to irreversible subcutaneous fibroadipose deposition in the affected extremity. As a result, patients experience chronic pain, decreased mobility and function, open wounds, and overall reduced quality-of-life. In Aim 1, I will examine how a stimulation of a signaling mediator which augments adipocyte differentiation may reduce overall fibroadipose deposition by preventing the proliferation of pathologic stem cell populations. In Aim 2, I will examine how inhibition of a pro-survival signaling mediator may impact adipocyte and pre-adipocyte survival. In the process, I seek to understand whether specific subsets of these cells are more likely to undergo apoptosis. Finally, in Aim 3, I seek to develop a local cell therapy which obviates the systemic adverse effects of therapies which modify cell differentiation or survival. In the process, I will have developed a therapy which is capable of secreting microRNA, paving the way for a new class of cell therapeutics. The career development award is indispensable for my maturation as a physician-scientist, to serve as a scientific and clinical leader performing research which is inspired by the challenges my patients face, rigorous in its evaluation of the underlying pathogenesis of this condition, and translational in its consideration of treatment strategies. I am supported by a team of mentors with expertise in stem cell and adipocyte biology, clinical lymphedema management, and in academic plastic surgery leadership. I am also supported by a team of additional scientific advisors with expertise in lymphedema biology, cell therapy, and translational medicine. The institution is committed to my success, with protected time for activities proposed in this award, laboratory space, salary support, and laboratory funding. During the 5-year career development award, I will build on my previous expertise with monitoring stem cell fate using lineage-tracing mouse models, and add new scientific expertise to my armamentarium with single-cell RNA sequencing and bioinformatics analysis. I will engage in workshops and seminars to build on my technical skillset, and develop essential laboratory leadership skills. Upon completion of my 4th year of the career development award, I will submit for my first R01 submission, with the goal of further advancing findings obtained during my career development award. Upon completion of the 5-year award period, I will expect to have established my scientific expertise in adipocyte biology, cell therapy, and lymphedema, and established my technical expertise in lineage-tracing and RNA sequencing, to contribute broadly to the scientific environment in my institution.