Bone marrow cell therapy for cardiac disease: Impact of donor age and infarction

骨髓细胞治疗心脏病：捐赠者年龄和梗塞的影响

• 批准号: 7990014
• 负责人: MATTHEW Lawrence SPRINGER
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990014
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Autologous; Bone Marrow; Bone Marrow Cells; Cardiac; Cell Therapy; Cells; Cellular Structures; Clinical; Data; Disease; Elderly; Experimental Models; Harvest; Heart; Heart Diseases; Heart failure; Impairment; Individual; Infarction; Inflammatory; Inflammatory Response; Length; Mus; Myocardial Infarction; Myocardium; Patients; Pharmaceutical Preparations; Preclinical Testing; Procedures; Research; Research Proposals; Solutions; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Work; age group; aged; base; cell type; implantation; patient population; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): The proposed research will determine how autologous cell therapy for myocardial infarction (MI) can be impaired by age and the MI itself, and how this impairment can be avoided. We and others have demonstrated that implantation of mouse bone marrow cells (BMCs) into mouse hearts after myocardial infarction (MI) can prevent the decline in cardiac function that would otherwise occur. However, while such experiments typically use young healthy donor mice, MI patients undergoing autologous cell therapy tend to be older and have had an MI. We have recently observed that BMCs from old donor mice lack this therapeutic capacity. Furthermore, in several age groups, we have compared healthy donor mice with those that have themselves had an MI, and find that BMCs from donors with MI are also therapeutically impaired. We will answer the following questions: What causes this age- and infarct-related impairment of the BMCs? Do the negative effects of donor age and disease work through different mechanisms? How can these negative effects be prevented in our experimental model? Most importantly, can such a solution be directly applied to current clinical autologous BMC therapy of the aged, post-MI patient population? Our general hypothesis is that MI increases the inflammatory state of the bone marrow and adds a deleterious component to the otherwise-beneficial bone marrow, whereas age decreases the beneficial component. Specifically, we will test the hypothesis that MI causes a systemic inflammatory response that increases the number or activation state of inflammatory cells in the bone marrow. The hyper-inflammatory BMCs are deleterious to the myocardium, and the problem can be circumvented by removing these cells prior to implantation. We will also test the hypothesis that donor age reduces the beneficial component of the bone marrow responsible for the BMCs' therapeutic effect, in contrast with the proposed increase in the deleterious component caused by donor MI. The data generated in this R21 will be used as the basis of more long-term research proposals, aimed at understanding the mechanistic details of how different age and disease states differentially affect the therapeutic capacity of cells in the bone marrow, and how these potential problems can be avoided in clinical cell therapy procedures. PUBLIC HEALTH RELEVANCE: Bone marrow cell delivery to the heart is a promising new treatment for heart attacks and heart failure that is the subject of intense clinical and preclinical testing. Because these cells are taken from the patient's own bone marrow, we will study how the therapeutic potential of bone marrow cells can be decreased in older individuals and those with heart disease. We will also attempt to prevent these problems by removing specific cells that we predict have accumulated in the bone marrow as a result of the age and disease.

描述（由申请人提供）：拟议的研究将确定年龄和 MI 本身如何损害心肌梗死（MI）的自体细胞疗法，以及如何避免这种损害。 我们和其他人已经证明，在心肌梗塞（MI）后将小鼠骨髓细胞（BMC）植入小鼠心脏可以防止本来会发生的心脏功能下降。然而，虽然此类实验通常使用年轻健康的供体小鼠，但接受自体细胞治疗的心肌梗死患者往往年龄较大并且患有心肌梗死。我们最近观察到来自年老供体小鼠的 BMC 缺乏这种治疗能力。此外，在几个年龄组中，我们将健康的供体小鼠与本身患有心肌梗死的小鼠进行了比较，发现患有心肌梗死的供体小鼠的 BMC 也受到治疗损伤。我们将回答以下问题：是什么导致了这种与年龄和梗塞相关的 BMC 损伤？捐赠者年龄和疾病的负面影响是否通过不同的机制发挥作用？在我们的实验模型中如何防止这些负面影响？最重要的是，这样的解决方案是否可以直接应用于当前老年、心梗后患者群体的临床自体BMC治疗？ 我们的一般假设是，心肌梗死会增加骨髓的炎症状态，并在原本有益的骨髓中添加有害成分，而年龄会减少有益成分。具体来说，我们将检验这样的假设：心肌梗死会引起全身炎症反应，从而增加骨髓中炎症细胞的数量或激活状态。高炎症的 BMC 对心肌有害，可以通过在植入前去除这些细胞来避免这个问题。我们还将检验以下假设：供体年龄会降低负责 BMC 治疗效果的骨髓有益成分，而与供体 MI 引起的有害成分的增加相反。 R21 中生成的数据将用作更长期研究计划的基础，旨在了解不同年龄和疾病状态如何不同地影响骨髓细胞的治疗能力的机制细节，以及这些潜在问题如何在临床细胞治疗过程中可以避免。 公众健康相关性：将骨髓细胞输送至心脏是治疗心脏病和心力衰竭的一种有前途的新疗法，这是严格的临床和临床前测试的主题。由于这些细胞取自患者自身的骨髓，因此我们将研究如何降低老年人和心脏病患者的骨髓细胞的治疗潜力。我们还将尝试通过去除我们预测由于年龄和疾病而在骨髓中积累的特定细胞来预防这些问题。