Dissecting the Human Diabetic Bone Marrow Niche

解剖人类糖尿病骨髓生态位

基本信息

批准号：
10572520
负责人：
Tammy Tran Nguyen
金额：
$ 16.46万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10572520
关键词：
Adipocytes Adipose tissue Affect Amputation Animals Automobile Driving Award Bone Marrow CD34 gene Cells Chondrocytes Coculture Techniques Communities Complement Cultured Cells Data Development Diabetes Mellitus Diabetic Foot Ulcer Disadvantaged Discipline Emergency Care Experimental Models Failure Flow Cytometry Funding Future Gene Expression Grant Harvest Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Immune Immune System Diseases Immune system Immunohistochemistry Immunology Immunotherapy Impaired wound healing Impairment In Vitro Infection Inflammatory Innate Immune System Knowledge LEPR gene Laboratories Learning Leptin Life Lower Extremity Massachusetts Measures Mediating Medical Medical Care Costs Mentors Mentorship Mesenchymal Stem Cells Metabolic Diseases Methods Mus Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Osteocytes Patients Play Pre-Clinical Model Property Regulatory Pathway Research Role Sample Size Scientist Signal Pathway Signal Transduction Stains Surgeon Systems Development Techniques Testing Tissues Training Translating Transplantation Type 2 diabetic Umbilical Cord Blood Universities Western Blotting Work cell type comparative cytokine diabetic diabetic patient disability healing human stem cells immune function in vivo in vivo Model leptin receptor lifetime risk macrophage medical schools model development monocyte mortality mortality risk mouse model non-diabetic novel novel therapeutics prevent receptor expression skills stem cell function stem cell population tissue culture transcriptome sequencing wound wound healing

项目摘要

PROJECT ABSTRACT Approximately one-third of all diabetic patients develop a diabetic foot ulcer (DFU), of which 50% will result in a lower extremity amputation due to infection. The medical cost, utilization of emergency care, medical disability, and increased mortality due to DFUs is disproportionately higher in disadvantaged communities. Current treatment for DFUs is only 50% effective at preventing amputation because we lack fundamental knowledge regarding the mechanisms driving the failure of DFUs to heal. Type 2 diabetes (T2D) is associated with impaired innate immunity function during wound healing. The innate immune system is primarily derived from bone marrow hematopoietic stem cells (HSCs). To study the effect of T2D on the development of human innate immunity, I have developed a novel method to harvest and expand human HSCs and mesenchymal progenitor cells (MSCs) directly from bone marrow tissue explants collected from T2D and non-T2D donors that underwent lower extremity amputation. The tissue explant culture recapitulates the bone marrow niche through the co-culture and expansion of human MSCs and HSCs. My preliminary data demonstrates that an adipocyte-rich bone marrow microenvironment comprises a specialized niche for a previously unrecognized HSC population and suggests that bone marrow adipocytes may influence the functional properties of the human innate immune system development through the leptin signaling pathway. The proposed work will define the effect of T2D on bone marrow-derived innate immunity development (Aim 1 and 2). These studies will be complemented by investigating the role of leptin, an inflammatory cytokine produced by adipocytes, in the dysregulation of normal immune cell development (Aim 3). This work will be performed under the continual mentorship of Dr. Silvia Corvera, an expert in adipose tissue signaling and metabolic disease. I will further build upon relationships with my co-mentors, Dr. Louis Messina, Dr. Michael Brehm, Dr. Jennifer Wang, and Dr. Katherine Fitzgerald, who are renowned for their knowledge and expertise in HSCs, humanized immune mouse models, innate immunity in diabetes, and immunology respectively. This work will be conducted at University of Massachusetts Chan School of Medicine. The results of the proposed work will provide fundamental understanding of the human diabetic innate immune system and have the potential to translate these findings into development of in vivo pre-clinical models for DFUs and novel immunotherapies (or other targeted treatments) to treat non-healing DFUs. If funded, this award will allow me to complete a rigorous training plan to expand my research across disciplines, learn new techniques, and acquire knowledge and skills to establish an independent laboratory focused on targeting the diabetic immune system to enhance wound healing, thereby ultimately preventing lower extremity amputations.

项目摘要大约三分之一的糖尿病患者会出现糖尿病足溃疡 (DFU)，其中 50% 会导致糖尿病足溃疡 (DFU) 因感染而下肢截肢。医疗费用、紧急护理的使用、医疗残疾以及在弱势社区，由于 DFU 导致的死亡率增加得不成比例。目前的治疗方法为 DFU 在预防截肢方面的效果只有 50%，因为我们缺乏关于截肢的基础知识导致 DFU 无法愈合的机制。 2 型糖尿病 (T2D) 与伤口愈合过程中先天免疫功能受损有关。与生俱来的免疫系统主要来源于骨髓造血干细胞（HSC）。研究 T2D 的影响关于人类先天免疫的发展，我开发了一种新的方法来收获和扩展人类直接取自 T2D 和 T2D 患者的骨髓组织外植体的 HSC 和间充质祖细胞 (MSC) 接受下肢截肢的非 T2D 捐献者。组织外植体培养再现骨通过人类 MSC 和 HSC 的共培养和扩增获得骨髓生态位。我的初步数据表明富含脂肪细胞的骨髓微环境包含一个以前未被识别的专门生态位 HSC 群体表明骨髓脂肪细胞可能影响人类的功能特性先天免疫系统通过瘦素信号通路发育。拟议的工作将确定 T2D 对骨髓源性先天免疫发育的影响（目标 1 和2）。这些研究将通过调查瘦素（一种产生的炎症细胞因子）的作用来补充。脂肪细胞导致正常免疫细胞发育失调（目标 3）。这项工作将在脂肪组织专家 Silvia Corvera 博士的持续指导下进行信号传导和代谢疾病。我将进一步巩固与我的共同导师路易斯·梅西纳博士、路易斯·梅西纳博士的关系。迈克尔·布雷姆 (Michael Brehm)、詹妮弗·王 (Jennifer Wang) 博士和凯瑟琳·菲茨杰拉德 (Katherine Fitzgerald) 博士因其知识和经验而闻名分别在造血干细胞、人源化免疫小鼠模型、糖尿病先天免疫和免疫学方面拥有专业知识。这项工作将在马萨诸塞大学陈医学院进行。拟议的结果这项工作将提供对人类糖尿病先天免疫系统的基本了解，并具有潜力将这些发现转化为 DFU 和新型免疫疗法的体内临床前模型的开发（或其他靶向治疗）来治疗不愈合的 DFU。如果获得资助，这个奖项将使我能够完成严格的培训计划，以扩展我的跨学科研究，学习新技术，并获得知识和技能建立一个独立的实验室，专注于针对糖尿病免疫系统以促进伤口愈合，从而最终防止下肢截肢。