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

改变继发性淋巴水肿纤维脂肪组织中的脂肪细胞和前脂肪细胞细胞命运

• 批准号: 10571049
• 负责人: Shailesh Agarwal
• 金额: $ 17.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571049
• 关键词: Achievement; Address; Adipocytes; Adipose tissue; Affect; Agonist; Apoptosis; Apoptotic; Autologous; Award; Bioinformatics; Biology; Cancer Patient; Cell Differentiation process; Cell Survival; Cell Therapy; Cells; Chronic; Clinical; Data; Deposition; Educational workshop; Engineering; Engraftment; Environment; Evaluation; Face; Fatty acid glycerol esters; Functional disorder; Funding; Goals; Hindlimb; Histologic; Impairment; Institution; K-Series Research Career Programs; Knockout Mice; Laboratories; Leadership; Limb structure; Local Therapy; Lymph; Lymphatic; Lymphedema; MAP3K7 gene; Maps; Mechanics; Mediator; Mentors; Mentorship; Mesenchymal; MicroRNAs; Modification; Monitor; Mus; Obesity; Oligonucleotides; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathology; Patients; Physicians; Plastic Surgical Procedures; Population; Predisposition; Process; Proliferating; Public Health; Quality of life; Research; Scientist; Signal Pathway; Signal Transduction; Site; Swelling; Tamoxifen; Technical Expertise; Therapeutic; Time; Tissues; Training; Translational Research; United States; Wages; adipocyte biology; adipocyte differentiation; adverse outcome; antagonist; career; cell type; chronic pain; exosome; expectation; experience; genetic signature; inhibitor; insight; mouse model; open wound; pharmacologic; prevent; receptor; research and development; rosiglitazone; secondary lymphedema; single-cell RNA sequencing; skills; stem cell biology; stem cell fate; stem cell population; stem cells; subcutaneous; success; symposium; therapy adverse effect; transcriptome sequencing; translational medicine; translational therapeutics; treatment strategy; uptake

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.

项目概要 继发性淋巴水肿是一种疾病，影响美国超过 500 万患者。 患有这种疾病的患者会出现淋巴滞留，并发展为不可逆的皮下 受影响肢体的纤维脂肪沉积。结果，患者经历慢性疼痛，减少 活动能力和功能、开放性伤口以及整体生活质量下降。在目标 1 中，我将研究如何 刺激增强脂肪细胞分化的信号传导介质可能会减少总体纤维脂肪 通过防止病理干细胞群的增殖来沉积。在目标 2 中，我将研究如何 抑制促存活信号介质可能会影响脂肪细胞和前脂肪细胞的存活。在此过程中， 我试图了解这些细胞的特定亚群是否更有可能发生细胞凋亡。最后，在 目标 3，我寻求开发一种局部细胞疗法，消除治疗的全身不良反应， 改变细胞分化或存活。在此过程中，我将开发出一种能够 分泌 microRNA，为新型细胞疗法铺平了道路。 职业发展奖对于我作为一名医师科学家的成熟、作为一名医生、科学家来说是不可或缺的。 科学和临床领导者进行的研究受到患者面临的挑战的启发，严谨 在评估这种情况的潜在发病机制时，以及在考虑转化时 治疗策略。我得到了具有干细胞和脂肪细胞生物学专业知识的导师团队的支持， 临床淋巴水肿管理，以及学术整形外科的领导地位。我也得到了团队的支持 拥有淋巴水肿生物学、细胞治疗和转化医学专业知识的其他科学顾问。 该机构致力于我的成功，并为该奖项中提议的活动提供受保护的时间，实验室 空间、薪资支持和实验室资金。在5年的职业发展奖期间，我将在我的 以前使用谱系追踪小鼠模型监测干细胞命运的专业知识，并添加了新的科学知识 我的军备库包括单细胞 RNA 测序和生物信息学分析方面的专业知识。我将从事 研讨会和研讨会，以增强我的技术技能，并培养基本的实验室领导技能。 完成第四年的职业发展奖后，我将提交我的第一份 R01 申请， 目标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 年的奖励期内，我希望能够在脂肪细胞生物学、细胞 治疗和淋巴水肿，并建立了我在谱系追踪和 RNA 测序方面的技术专长，以 为我所在机构的科学环境做出广泛贡献。