Pharmacological rejuvenation of aged hematopoietic stem cells.

老化造血干细胞的药理复兴。

基本信息

批准号：
8370848
负责人：
HARTMUT GEIGER
金额：
$ 36.14万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8370848
关键词：
Affect Age Aging Aging-Related Process Anemia Animals Biological Models Blood Blood Cells Cell Aging Cell Lineage Cell Maintenance Cells Chemicals Chemistry Cognitive aging Complex Country Data Development Disease Docking Elderly Erythropoiesis Family Future Generations Genes Genomics Genotype Guanosine Triphosphate Phosphohydrolases Harvest Hematopoietic Hematopoietic stem cells Homeostasis Human Incidence Intervention Intestines Knowledge Lead Link Longevity Lymphoid Medical Medical Economics Molecular Molecular Profiling Mononuclear Morbidity - disease rate Mus Muscle Muscle satellite cell Myeloid Cells Myeloid Leukemia Natural regeneration One-Step dentin bonding system Pharmaceutical Chemistry Phenotype Play Population Prevention Procedures Production Property Publications Publishing Recording of previous events Rejuvenation Role Stem cells Structure System Technology Therapeutic Tissues adult stem cell age related aged analog anti aging base cell age commercialization design fitness functional decline genome wide association study immune function improved inhibitor/antagonist innovation mouse model novel organ regeneration prevent rho rho GTP-Binding Proteins self-renewal social therapeutic target tissue regeneration trend

项目摘要

DESCRIPTION (provided by applicant): The demographic development in most Western countries predicts that age-associated diseases and their prevention will become an important social, economic and medical topic. Somatic stem cell activity is critical for tissue regeneration. There is a successive age-dependent functional decline in hematopoietic, intestinal and muscle stem cell quality, impairing tissue homeostasis and regeneration. Hematopoietic stem cells (HSCs) harvested from young and aged animals show quantitative differences that are in part intrinsic to HSCs. Aged HSCs show reduced self-renewal activity. Aging also affects the differentiation potential of HSCs. Many studies have demonstrated that aged HSCs are deficient in their ability to support erythropoiesis and do not efficiently generate B-lymphoid progeny but are better at supporting the myeloid cell lineage. It is assumed that the decreased HSC quality with age is at least in part the underlying cause of anemia, impaired immune function and increased incidence of myeloid leukemia in the elderly, all of which pose a significant medical problem. The small Rho family GTPase Cdc42 plays a critical role in regulating HSCs. Genome-wide association studies of human longevity have recently identified Cdc42 as the top over- expressed gene in mononuclear hematopoietic cells associated with morbidity and aging3. Importantly, pharmacological inhibition of Cdc42 activity in aged HSCs by the novel compound CASIN rejuvenates the functional of chronologically aged HSCs. Thus the product/procedure that we will focus on is that CASIN, a specific inhibitor of Cdc42 activity, may rejuvenate the function of chronologically aged HSCs. This is a novel and innovative approach as it is among the first targeted pharmacological therapies reverting aging of stem cells. PUBLIC HEALTH RELEVANCE: Stem cell activity is critical for tissue and organ regeneration. There is a successive age-dependent functional decline in hematopoietic, intestinal and muscle stem cell quality, impairing tissue homeostasis and regeneration, which pose a significant medical problem in the elderly. In this application we will focus on developing a proof of principle, inhibition of the small Rho GTPase Cdc42 in hematopoietic stem cells by a chemical compound CASIN, into a novel product to rejuvenate the function of chronologically aged hematopoietic stem cells. This exciting technology may prevent or treat age-related functional decline of blood production to benefit the lives of older adults.

描述（由申请人提供）：大多数西方国家的人口发展预测，与年龄相关的疾病及其预防将成为一个重要的社会、经济和医学话题。成体干细胞活性对于组织再生至关重要。随着年龄的增长，造血、肠道和肌肉干细胞质量会出现连续性功能下降，损害组织稳态和再生。从年轻和年老动物身上采集的造血干细胞 (HSC) 表现出数量上的差异，这在一定程度上是 HSC 固有的。老化的 HSC 自我更新活性降低。衰老也会影响造血干细胞的分化潜力。许多研究表明，老化的 HSC 缺乏支持红细胞生成的能力，并且不能有效地产生 B 淋巴细胞后代，但更擅长支持骨髓细胞谱系。据推测，随着年龄的增长，HSC 质量下降至少部分是老年人贫血、免疫功能受损和髓性白血病发病率增加的根本原因，所有这些都构成了重大的医学问题。小 Rho 家族 GTPase Cdc42 在调节 HSC 中发挥着关键作用。人类长寿的全基因组关联研究最近发现 Cdc42 是单核造血细胞中与发病和衰老相关的最高过度表达基因3。重要的是，新型化合物 CASIN 对老化 HSC 中 Cdc42 活性的药理学抑制可恢复按时间顺序老化的 HSC 的功能。因此，我们将重点关注的产品/程序是 CASIN，一种 Cdc42 活性的特异性抑制剂，可以恢复按时间顺序老化的 HSC 的功能。这是一种新颖且创新的方法，因为它是第一个逆转干细胞衰老的靶向药物疗法之一。公共卫生相关性：干细胞活性对于组织和器官再生至关重要。造血、肠道和肌肉干细胞质量随着年龄的增长而不断下降，损害组织稳态和再生，这给老年人带来了重大的医学问题。在此应用中，我们将重点开发原理证明，通过化学化合物 CASIN 抑制造血干细胞中的小 Rho GTPase Cdc42，将其开发为一种新产品，以恢复按时间顺序老化的造血干细胞的功能。这项令人兴奋的技术可以预防或治疗与年龄相关的造血功能下降，从而造福老年人的生活。