Effects of Metabolic Disorders on Bone Marrow-Derived Cell Function

代谢紊乱对骨髓来源细胞功能的影响

• 批准号: 8063969
• 负责人: GINA C SCHATTEMAN
• 金额: $ 31.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063969
• 关键词: Address; Animal Model; Attenuated; Autologous; Biological Assay; Blood Vessels; Blood capillaries; Bone Marrow; Burn injury; CCL2 gene; Cell Therapy; Cell physiology; Cells; Chemotactic Factors; Chronic; Clinical Trials; Data; Diabetes Mellitus; Diabetic mouse; Dyslipidemias; Effectiveness; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidemic; Exhibits; Foot Ulcer; Genes; Goals; Growth; Growth Factor; Healed; Hindlimb; Impaired wound healing; Individual; Interleukin-1; Interleukin-12; Knock-out; Knockout Mice; Lead; Measures; Mediating; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular Mechanisms of Action; Mus; Muscle; Myocardial Infarction; Obesity; Pathway interactions; Patients; Peripheral Vascular Diseases; Phase; Prevention; Principal Investigator; Production; Proteins; Regulatory Pathway; Risk; Role; Skin; Stroke; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Tumor Necrosis Factor-alpha; Ulcer; Vascular Diseases; Vascular Endothelial Growth Factor A; Vascularization; Western Blotting; Work; Wound Healing; arteriole; base; capillary; healing; high risk; injured; monocyte; mouse model; non-diabetic; programs; public health relevance; research study; response; wound

DESCRIPTION (provided by applicant): Diabetes, obesity, and dyslipidemia are epidemic in the U.S. and are associated with increased risk for stroke, myocardial infarction, peripheral vascular disease, and foot ulcers. Thus, there is immense need for better therapies to stimulate vascular growth in the treatment of these conditions. Bone marrow-derived cells (BMDCs) are being developed as therapeutic agents in this application. Unfortunately diabetes and metabolic syndrome damage BMDCs rendering them at best modestly pro- and at worst, anti-angiogenic. So, maximization of the therapeutic efficacy of BMDCs may require manipulation of the BMDCs or adjunct therapies. To accomplish this requires an understanding of molecular mechanisms of action of BMDCs and identification of factors that modulate their effectiveness. In studies of healthy mice and Leprdb mice (i.e., diabetic mice with metabolic syndrome) we identified four molecules, tumor necrosis factor alpha (TNF1), interleukin 12 (IL-12), monocyte chemoattractant factor 1 (MCP-1), and vascular endothelial growth factor A (VEGF-A) that share a common regulatory pathway that appears to regulate BMDC mediated vascular growth. This study will define the role of these molecules and their downstream targets in BMDC mediated tissue vascularization. Our aims are to determine if a reduction in the ability of BMDCs to 1) secrete TNF1, IL-12, or MCP-1; 2) induce TNF1, IL-12, or MCP-1; or 3) induce downstream targets of TNF1, IL-12, or MCP-1 limits their capacity to promote growth of capillaries, arterioles, or collaterals. The effects of the loss of these factors on BMDC induced vascular growth will be studied in the ischemic hindlimb and skin wound models in Leprdb mice and chimeric Leprdb mice whose bone marrow has been replaced with cells from and TNF1, IL-12, or MCP-1 knockout mice. By treating mice with BMDCs from healthy, TNF1, IL-12, or MCP-1 knockout mice and performing rescue experiments we will identify 1) which of the studied factors are critical for BMDC mediated growth and 2) which might be used therapeutically as adjuncts to BMDC therapy in patients with poorly functioning BMDCs. BMDCs are already in use in early phase clinical trials, but there is little understanding of why cell therapy succeeds in some and fail in other patients. Our ultimate goals are to understand this dichotomy, to provide a more rational basis for selecting patients who are likely to benefit from BMDC therapy, and identify possible adjunct therapies to potentiate the effects of BMDCs in those whose own BMDCs provide little therapeutic benefit. PUBLIC HEALTH RELEVANCE: This work could lead to better treatment of heart attacks, strokes, and burns as well as prevention of chronic ulcers, particularly in people who are obese and those with diabetes.

描述（由申请人提供）：糖尿病、肥胖症和血脂异常在美国很流行，并且与中风、心肌梗死、外周血管疾病和足部溃疡的风险增加相关。因此，在治疗这些病症时非常需要更好的疗法来刺激血管生长。骨髓源性细胞 (BMDC) 正在被开发为该应用中的治疗剂。不幸的是，糖尿病和代谢综合征会损害 BMDC，使其在最好的情况下具有适度的促血管生成作用，而在最坏的情况下则具有抗血管生成作用。因此，最大化 BMDC 的治疗功效可能需要对 BMDC 进行操作或辅助疗法。要实现这一目标，需要了解 BMDC 的分子作用机制并确定调节其有效性的因素。在对健康小鼠和 Leprdb 小鼠（即患有代谢综合征的糖尿病小鼠）的研究中，我们发现了四种分子：肿瘤坏死因子 α (TNF1)、白细胞介素 12 (IL-12)、单核细胞趋化因子 1 (MCP-1) 和血管内皮生长因子 A (VEGF-A)，它们共享似乎调节的共同调节途径。 BMDC 介导血管生长。这项研究将定义这些分子及其下游靶标在 BMDC 介导的组织血管化中的作用。我们的目标是确定 BMDC 的能力是否降低：1) 分泌 TNF1、IL-12 或 MCP-1； 2)诱导TNF1、IL-12或MCP-1； 3) 诱导 TNF1、IL-12 或 MCP-1 的下游靶点限制其促进毛细血管、小动脉或侧支循环生长的能力。这些因子的丧失对 BMDC 诱导的血管生长的影响将在 Leprdb 小鼠和嵌合 Leprdb 小鼠的缺血后肢和皮肤伤口模型中进行研究，这些小鼠的骨髓已被 TNF1、IL-12 或 MCP-1 敲除小鼠的细胞取代。通过使用健康的 TNF1、IL-12 或 MCP-1 敲除小鼠的 BMDC 治疗小鼠并进行救援实验，我们将确定 1) 哪些研究因素对于 BMDC 介导的生长至关重要，2) 哪些因素可能在治疗上作为 BMDC 功能不良患者的 BMDC 治疗的辅助手段。 BMDC 已用于早期临床试验，但人们对为什么细胞疗法在某些患者中成功而在其他患者中失败的原因知之甚少。我们的最终目标是了解这种二分法，为选择可能受益于 BMDC 治疗的患者提供更合理的基础，并确定可能的辅助疗法，以增强 BMDC 对那些自身 BMDC 几乎没有治疗益处的患者的作用。 公众健康相关性：这项工作可以更好地治疗心脏病、中风和烧伤以及预防慢性溃疡，特别是对于肥胖者和糖尿病患者。