Combined effects of aging and type 2 diabetes on wound healing in a humanized mouse model

衰老和 2 型糖尿病对人源化小鼠模型伤口愈合的综合影响

• 批准号: 10266842
• 负责人: Louis Michael Messina
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266842
• 关键词: Address; Affect; Age; Aging; Amputation; Animal Model; Aorta; Arginine; Arterial Fatty Streak; Atherosclerosis; Basic Science; Becaplermin; Biological Availability; Biological Response Modifier Therapy; CD34 gene; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Clinical Research; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Disease; Elderly; Engraftment; FDA approved; Failure; Foot Ulcer; Gastrocnemius Muscle; Gene Expression; Goals; Hematopoietic stem cells; Human; Immune; Immune system; Impaired wound healing; Impairment; Inflammatory; Malignant Neoplasms; Modeling; Mus; Natural Immunity; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oxidative Stress; Pathogenesis; Patients; Persons; Phase; Phenotype; Population; Publishing; Reporting; Research; Research Personnel; Risk; Risk Factors; Rodent; Scientist; Supplementation; Testing; Translational Research; Type 2 diabetic; Work; Wound models; age effect; aged; ascorbate; base; cardiovascular risk factor; cell age; chronic ulcer; chronic wound; clinically relevant; diabetic; diabetic patient; diabetic ulcer; hematopoietic stem cell differentiation; human disease; humanized mouse; hypercholesterolemia; immune function; improved; insight; lifetime risk; macrophage; monocyte; mortality; mouse model; non-healing wounds; novel; novel therapeutic intervention; oxidant stress; research and development; risk sharing; stem cell therapy; targeted treatment; tetrahydrobiopterin; therapeutic evaluation; therapy development; tool; wound; wound healing; wound treatment

Abstract Aging is a powerful risk factor for the development of chronic, non-healing foot ulcers in people with type 2 diabetes (T2DM). Diabetic foot ulcers in older adults with T2DM have devastating consequences, leading to increased risks of amputation and all-cause mortality. There is a compelling, unmet need to develop therapies to treat these non-healing wounds in this population; however, an appropriate animal model for use in the development of biotherapeutics and stem cell therapies with a high degree of translatability to human disease does not exist. Therefore, the overall goal of this proposal is to develop an aged-T2DM humanized mouse model to study the mechanisms by which the combined effects of aging and T2DM dysregulate the human immune system of T2DM patients during wound healing and to test therapeutics based on these new insights. To achieve this goal, two Specific Aims are proposed. The purpose of Specific Aim 1 is to develop a humanized mouse model engrafted with CD34+ hematopoietic stem cells (HSCs) from aged-T2DM human donors to study wound healing. The hypothesis is that humanized mice engrafted with CD34+ HSCs from older adults with diabetes faithfully recapitulate the non-healing wound phenotype and skewed polarization of wound- infiltrating macrophages that has been documented in human T2DM patients. This model is based on our published and unpublished findings that T2DM and aging impair wound healing by an oxidant stress- dependent HSC autonomous mechanism. Thus, the aging-T2DM-associated impairment in wound healing will be conferred by the donor HSCs from aged-T2DM patients. The purpose of Specific Aim 2 is to determine the effect of ATLAS therapy on wound healing in humanized mice engrafted with aged-T2DM HSCs. The hypothesis is that ATLAS treatment of HSCs derived from aged T2DM human donors prior to engraftment into NSG-SGM3 mice reduces HSC oxidant stress and increases nitric oxide bioavailability that restores normal macrophage number and polarization in wounds. Our results show that in a T2DM murine model of wound healing ATLAS, a combination of L-arginine, tetrahydrobiopterin, and L-ascorbate, decreases HSC oxidative stress and increases HSC NO bioavailability that restores normal wound healing. The development of the proposed humanized mouse model bridges a major gap between murine wound healing models and human non-healing foot ulcers in older adults with T2DM; thus, the creation of a highly translatable tool to develop novel biological therapies to treat non-healing wounds in older adults with T2DM fulfills a major unmet need for these patients. As a consequence of the results of this project, we hope to greatly reduce the suffering from this devasting problem that disproportionately affects older adults worldwide.

抽象的 衰老是2型患者慢性，非治疗足溃疡发展的有力危险因素 糖尿病（T2DM）。 T2DM老年人的糖尿病足溃疡具有毁灭性后果，导致 截肢和全因死亡率的风险增加。有一个令人信服的，未满足的需要开发疗法 治疗这些人群中的这些非愈合伤口；但是，适合在 具有高度转化为人类疾病的生物治疗剂和干细胞疗法的开发 不存在。因此，该提案的总体目标是开发老化的T2DM人源化鼠标 研究衰老和T2DM综合作用使人类失调的结合作用的机制 T2DM患者在伤口愈合过程中的免疫系统和基于这些新见解测试治疗剂。 为了实现这一目标，提出了两个具体目标。特定目的1的目的是开发人性化的 植入来自老年T2DM人类供体的CD34+造血干细胞（HSC）的小鼠模型 伤口愈合。假设是，植入了来自老年人的CD34+ HSC的人源化小鼠 糖尿病忠实地概括了非愈合的伤口表型和伤口的极化 在人类T2DM患者中已记录的巨噬细胞浸润。该模型基于我们 发表且未发表的发现，T2DM和衰老会损害氧化剂应激的伤口愈合 依赖的HSC自主机制。因此，伤口愈合中与衰老-T2DM相关的损伤将 由老年T2DM患者的供体HSC授予。特定目标2的目的是确定 Atlas治疗对植入老年T2DM HSC的人源性小鼠伤口愈合的影响。这 假设是，在植入之前从老化的T2DM人类捐助者中得出的HSC的地图集处理 NSG-SGM3小鼠减少了HSC氧化剂应激，并增加一氧化氮生物利用度，以恢复正常 巨噬细胞数量和伤口极化。我们的结果表明，在T2DM的伤口鼠模型中 L-精氨酸，四氢无生蛋白和L-抗坏血酸的愈合地图集降低了HSC氧化 压力并增加HSC没有生物利用度可以恢复正常的伤口愈合。发展 拟议的人源化小鼠模型桥接了鼠伤口愈合模型与人类的主要差距 T2DM老年人的非治疗足溃疡；因此，创建高度翻译的工具来开发 T2DM老年人治疗非治疗伤口的新型生物疗法满足了主要的需求 对于这些患者。由于该项目的结果，我们希望大大减少 这个毁灭性的问题不成比例地影响全世界的老年人。