Targeting HIF-1 alpha Dysfunction in Complications of Aging

针对衰老并发症中的 HIF-1 α 功能障碍

• 批准号: 8253690
• 负责人: GEOFFREY C GURTNER
• 金额: $ 32.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253690
• 关键词: Age; Aging; Animals; Area; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cell Aging; Cell Differentiation process; Characteristics; Clinical; Communication; Comorbidity; Complex; Cutaneous; Decubitus ulcer; Elderly; Event; FDA approved; Functional disorder; Funding; Genes; HIF1A gene; Hypoxia; Impaired wound healing; Impairment; In Vitro; Ischemia; Knock-out; Knockout Mice; Laboratories; Link; Mediating; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Necrosis; Neuraxis; Nuclear; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Vascular Diseases; Pharmaceutical Preparations; Phenotype; Population; Populations at Risk; Reactive Oxygen Species; Recovery; Recruitment Activity; Risk Factors; Role; Seeds; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Soil; Stabilizing Agents; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Stunned Myocardium; Superoxide Dismutase; System; Therapeutic; Thick; Time; Tissue Survival; Tissues; Transgenic Mice; Transgenic Model; United States; Vascular Dementia; Vascular Diseases; Wound Healing; age related; aged; aging population; angiogenesis; cell age; high risk; hypoxia inducible factor 1; improved; in vivo; insight; mortality; neovascular; neovascularization; novel; prevent; public health relevance; research study; response; small molecule; transcription factor; treatment strategy; vasculogenesis

DESCRIPTION (provided by applicant): Effective neovascularization, or new blood vessel formation, is critical for both wound healing and tissue survival following ischemia. Neovascularization occurs via two distinct pathways: the sprouting of new blood vessels from existing vessels (angiogenesis) and the recruitment, proliferation and assembly of bone-marrow derived vascular progenitor cells into new vessels (vasculogenesis). Through complex signaling mechanisms, ischemic tissue (the "soil") actively recruits circulating progenitor cells ("the seeds") out of the bone marrow and into the area of ischemia to initiate proliferation and differentiation of these cells into new blood vessels. We and others have shown that aging significantly impairs this communication between ischemic tissue and circulating progenitor cells and leads to dysfunctional vasculogenesis. In aged patients, this dysfunction hinders recovery from ischemic insults such as myocardial infarction or stroke and impairs wound healing, which leads to poor clinical outcomes. In this proposal, we will capitalize on our laboratory's expertise by focusing on impaired wound healing as a representative example of dysfunctional vasculogenesis in aging. During the prior funding period, we demonstrated that aging markedly diminishes the activity of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1a), resulting in reduced expression of multiple vasculogenic genes and a dysfunctional response to ischemia. It is our fundamental hypothesis that dysfunction in HIF-1a-mediated neovascularization underlies the vascular complications of aging, and that identification and reversal of this dysfunction will improve recovery from ischemia in aged patients. In this proposal, we will expand on our previous findings to precisely define the causative mechanisms underlying HIF-1a dysfunction in hypoxic tissue (SA1), determine the role of increased oxidative stress in age-related dysfunctional vasculogenesis (SA2), and refine a therapeutic strategy to restore normal neovascularization to aged patients (SA3). PUBLIC HEALTH RELEVANCE: Aging is a known risk factor for impaired wound healing and poor tissue recovery following an ischemic insult. Accordingly, advanced age is associated with a high risk of vascular comorbidities including cardiovascular disease, peripheral vascular disease, stroke, and vascular dementia. After myocardial infarction or stroke in aged patients, neovascularization is insufficient to properly rescue "stunned" myocardium or the central nervous system, thereby increasing morbidity and mortality. With a rapidly aging population in the United States, the population at risk for complications is expected to continue to grow. Ameliorating HIF-1a dysfunction in the aged would be expected to reduce morbidity and mortality in aged populations by improving the neovascularization response to ischemic events (e.g. myocardial infarction and stroke).

描述（由申请人提供）：缺血后的伤口愈合和组织存活至关重要。新血管化是通过两种不同的途径进行的：现有血管的新血管（血管生成）以及骨髓衍生的血管祖细胞的募集，增殖和组装成新容器（血管生成）。通过复杂的信号传导机制，缺血组织（“土壤”）积极地募集祖细胞（“种子”）从骨髓中循环到缺血区域，以将这些细胞的增殖和分化为新的血管。我们和其他人已经表明，衰老会严重损害缺血组织和循环祖细胞之间的这种通信，并导致功能障碍的血管生成。在老年患者中，这种功能障碍阻碍了从心肌梗塞或中风等缺血性损伤中恢复，并损害伤口愈合，从而导致临床结果不佳。在此提案中，我们将通过关注伤口愈合受损的疾病来利用实验室的专业知识，这是衰老中功能失调的血管生成的代表性例子。在以前的资金期间，我们证明衰老显着降低了转录因子低氧诱导因子-1α（HIF-1A）的活性，从而导致多个血管生成基因的表达降低，并且对缺血性疾病的功能障碍反应。我们的基本假设是，HIF-1A介导的新血管化功能障碍是衰老的血管并发症的基础，并且这种功能障碍的鉴定和逆转将改善老年患者缺血的恢复。在这一提议中，我们将扩展我们以前的发现，以精确定义缺氧组织中HIF-1A功能障碍的原因（SA1），确定氧化应激增加在年龄相关功能性血管生成（SA2）中增加的作用（SA2），并改善了恢复正常的卫生治疗患者的治疗策略（SA）（SA3）。 公共卫生相关性：衰老是缺血性损伤后伤口愈合受损和组织恢复不良的危险因素。因此，高级年龄与血管合并症的高风险有关，包括心血管疾病，周围血管疾病，中风和血管痴呆。在老年患者的心肌梗塞或中风后，新血管形成不足以正确挽救“震惊”的心肌或中枢神经系统，从而增加发病率和死亡率。随着美国人口迅速衰老的人口，面临并发症风险的人口预计将继续增长。预计老年人的HIF-1A功能障碍有望通过改善对缺血性事件的新血管形成反应（例如心肌梗塞和中风）来降低老年人群的发病率和死亡率。