Dissecting the Human Diabetic Bone Marrow Niche

解剖人类糖尿病骨髓生态位

• 批准号: 10689209
• 负责人: Tammy Tran Nguyen
• 金额: $ 16.31万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/10689209
• 关键词: Adipocytes; Adipose tissue; Affect; Amputation; Animals; Automobile Driving; Award; Bone Marrow; CD34 gene; Cells; Chondrocytes; Coculture Techniques; Complement; Data; Development; Diabetes Mellitus; Diabetic Foot Ulcer; 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; Knowledge acquisition; LEPR gene; Laboratories; Learning; Leptin; Life; Lower Extremity; Macrophage; 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; diabetic ulcer; disability; healing; human stem cells; immune function; in vivo; in vivo Model; leptin receptor; lifetime risk; medical schools; model development; monocyte; mortality; mortality risk; mouse model; neighborhood disadvantage; non-diabetic; novel; novel therapeutics; prevent; receptor expression; skill acquisition; skills; stem cell function; stem cell population; stem cells; tissue culture; transcriptome sequencing; wound; wound healing

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发展为糖尿病足溃疡(DFU)，其中50%会导致 因感染截肢。医疗费用、紧急护理的利用率、医疗残疾以及 在弱势社区，由于DFU而增加的死亡率高得不成比例。目前的治疗方法是 DFU在预防截肢方面只有50%有效，因为我们缺乏关于 导致DFU无法愈合的机制。 2型糖尿病(T2D)与创面愈合过程中先天免疫功能受损有关。先天的 免疫系统主要来源于骨髓造血干细胞。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获取和扩大人类 直接从T2D和T2D采集的骨髓组织外植体中分离培养HSCs和MSCs 接受截肢手术的非T2D供者。组织块培养重建骨 通过人骨髓间充质干细胞和造血干细胞的共培养和扩增形成骨髓生态位。我的初步数据显示 富含脂肪细胞的骨髓微环境包括以前未被认识到的 HSC群体，提示骨髓脂肪细胞可能影响人类的功能特性 先天免疫系统发育通过瘦素信号通路。 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)。这些研究将通过研究瘦素的作用来补充，瘦素是一种产生的炎性细胞因子 通过脂肪细胞，在正常免疫细胞发育的失调中(目标3)。 这项工作将在脂肪组织专家西尔维娅·科维拉博士的持续指导下进行 信号和代谢性疾病。我将进一步加强与我的合作导师路易斯·梅西纳博士、路易斯·梅西纳博士、路易斯·梅西纳博士、路易斯·梅西纳博士、 迈克尔·布雷姆、珍妮弗·王博士和凯瑟琳·菲茨杰拉德博士，他们以其知识和 分别在造血干细胞、人源化免疫小鼠模型、糖尿病的先天免疫和免疫学方面具有专长。 这项工作将在马萨诸塞大学陈医学院进行。建议的研究结果 这项工作将提供对人类糖尿病先天免疫系统的基本了解，并有可能 将这些发现转化为DFU体内临床前模型的开发和新的免疫疗法(或 其他有针对性的治疗)来治疗无法愈合的DFU。如果得到资助，这个奖项将让我完成一项严格的 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，以 建立一个独立的实验室，专注于糖尿病免疫系统，以促进伤口愈合， 从而最终防止截肢。