HSC Diversity, in aging, ontogeny, and transformation

HSC 衰老、个体发育和转化方面的多样性

基本信息

批准号：
8913718
负责人：
IRVING L. WEISSMAN
金额：
$ 40.93万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913718
关键词：
2 year old Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Affect Age Aged, 80 and over Aging Anemia Automobile Driving B-Lymphocytes Blood Blood Cells Blood Platelets Blood coagulation Bone Marrow Cell Cycle Cell Lineage Cells Characteristics Color Data Development Disease Dysmyelopoietic Syndromes Elderly Elements Embryo Embryonic Development Equilibrium Erythrocytes Feedback Gene Expression Profile Growth Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Hemorrhage Hereditary Disease Homing Behavior Human Immune System Diseases In Situ In Vitro Individual Infection Inherited Inner Cell Mass Lead Life Location Lymphocyte Lymphoid Lymphoid Cell Lymphoma Malignant - descriptor Malignant Neoplasms Measures Memory Methods Modeling Molecular Molecular Abnormality Mus Mutation Myelogenous Myeloid Cells Myeloid Leukemia Natural Killer Cells Outcome Oxygen PTPRC gene Parabiosis Patients Physiological Predisposition Preleukemia Premalignant Prevalence Production Property Public Health RNA Sequences Reporter Role Signal Transduction Staging Stem cells Surface System T-Lymphocyte Testing Thymic Lymphoma Time Tissues Umbilical Cord Blood Untranslated RNA Wild Type Mouse age related aged base blastocyst cell type congenic daughter cell effective therapy embryonic stem cell fighting granulocyte human RNA sequencing human subject in vivo leukemia leukemia/lymphoma leukemogenesis life history macrophage novel postnatal prevent progenitor public health relevance research study self-renewal stem stem cell population targeted treatment transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The blood system provides oxygen and nourishment to the body, and also contains cells that protect against infections, cancers, and blood loss. The appropriate production of all blood cells derives from a tiny fraction [~1 in 20,000] of blood forming cells in the adult bone marrow called blood forming stem cells. These stem cells are the only blood forming cells that can make more blood forming stem cells, a property called self-renewal. The stem cell transitions through many intermediate steps before giving rise to mature blood cell types-which are generally classified into two groups: myeloid (red blood cells [RBCs], platelets, granulocytes and macrophages) and lymphoid (B, T and NK cells) cells. At each successive step, there is a cell that becomes increasingly specialized by including some fates and excluding others. We wish to inquire why some blood forming stem cells, predominant in young mice and people, at the single cell level make roughly equivalent numbers of lymphoid and myeloid cells (balanced); and why other single stem cells, predominant in aged mice and humans, make very few new lymphoid cells, and make many more myeloid cells (myeloid-bias). Our preliminary evidence favors the hypothesis that a balanced stem cell is always balanced, no matter the age of the individual, while a myeloid biased stem cell is always biased; and these myeloid biased stem cells have a selective advantage in the aging individual. The experiments we describe provide multiple ways to answer this question in humans and mice. For example, in mice we have developed a method wherein we can determine the location and life history of single cells and their clonal progeny without the need to isolate them outside the body to study their properties. We bring all of these approaches to study how stem cells get their bias, move through the body, and how they are affected-and how their progenitor daughter cells are affected in normal blood formation, in genetic diseases of the blood, and in the development of preleukemias and leukemias. A number of blood diseases such as loss of oxygen carrying RBCs, or critical blood-clotting elements, or infection fighting cells can occur, usually due to inherited or acquired genetic abnormalities. We have shown, for example, that in human preleukemias the genetic changes that characterize these diseases, all occur in the single stem cells, some of which expand to make clones. Some clones eventually accumulate more mutations, so it is possible to determine the order of mutations for a particular patient and the patient's disease. In some preleukemias, such as in myelodysplastic syndrome [MDS], where there is a deficiency of one or more types of the mature blood cells, the individual mutations and order of addition of those mutations give strong clues about the cause of that cell's deficiency. When the preleukemic MDS clone progresses to acute leukemia, we have identified the kinds of mutations consistent with the progression and wild growth of the leukemia. Thus following the stages of normal blood cell development and analyzing the associated genetic changes can lead to better understanding of the cancer [or other blood diseases] and lead to new effective therapies.

描述（由申请人提供）：血液系统为身体提供氧气和营养，还含有防止感染、癌症和失血的细胞。所有血细胞的适当产生都来自一小部分[约两万分之一]。成人骨髓中的造血细胞称为造血干细胞，这些干细胞是唯一可以产生更多造血干细胞的造血细胞，这种特性称为自我更新。产生成熟的血细胞类型，通常分为两类：骨髓细胞（红细胞 [RBC]、血小板、粒细胞和巨噬细胞）和淋巴细胞（B、T 和 NK 细胞）。一种通过包含某些命运并排除其他命运而变得越来越特化的细胞，我们希望了解为什么一些造血干细胞（主要存在于年轻小鼠和人类中）在单细胞水平上产生大致相同数量的淋巴和骨髓细胞。（平衡）；以及为什么其他单一干细胞（主要存在于老年小鼠和人类中）很少产生新的淋巴细胞，而产生更多的骨髓细胞（骨髓偏向性），我们的初步证据支持这样的假设：平衡的干细胞始终是平衡的。平衡，无论个体的年龄如何，而偏向骨髓的干细胞总是有偏向的；并且这些偏向骨髓的干细胞在衰老个体中具有选择性优势，我们描述的实验提供了多种方法来回答人类和小鼠的这个问题。。例如，在小鼠中，我们开发了一种方法，这样我们就可以确定单细胞及其克隆后代的位置和生命史，而无需将它们分离到体外来研究它们的特性。我们利用所有这些方法来研究它们是如何干的。细胞获得它们的偏向，在体内移动，以及它们如何受到影响，以及它们的祖细胞在正常血液形成、血液遗传疾病以及白血病前期和白血病的发展中如何受到影响。例如携带氧气的损失红细胞、关键凝血因子或抗感染细胞的出现通常是由于遗传或获得性基因异常，例如，在人类白血病前期，表征这些疾病的基因变化都发生在单个干细胞中。一些克隆最终会积累更多的突变，因此可以确定特定患者和患者疾病的突变顺序，例如骨髓增生异常综合征。 [MDS]，其中一种或多种类型的成熟血细胞缺乏，当白血病前期 MDS 克隆发展为急性白血病时，单个突变和这些突变的添加顺序为该细胞缺乏的原因提供了强有力的线索。，我们已经确定了与白血病的进展和野生生长一致的突变类型，因此跟踪正常血细胞发育的阶段和相关的遗传变化可以更好地了解癌症[或其他血液疾病]并导致。新的有效疗法。