FUNCTION OF CD34 AND ITS ROLE IN STEM CELL BIOLOGY

造血干细胞是一种罕见的细胞群体，具有 独特的潜力，以帮助细胞治疗血液恶性肿瘤， 骨髓衰竭疾病，以及基因治疗。这些细胞 最常使用CD 34抗原分离。CD 34表达 特别是这些细胞，但其功能尚不清楚。是否CD 34 功能在干细胞生物学中扮演的角色是一个重要问题。 此外，CD 34在最早期干细胞上的表达仍然不确定， 尽管有充分的证据表明更成熟的干细胞表达CD 34。 然而，它可能是至关重要的疾病与干细胞 使用最原始的干细胞进行细胞移植 疗法我们的第一个具体目标是研究CD 34表达的作用， 用于原始茎的自我更新、增殖和分化 细胞这将涉及将CD 34无效干细胞移植到 将正常小鼠和正常细胞转化为无效小鼠，以测试 这些空细胞。在这种情况下，我们还将研究恢复 内源性CD 34空干细胞对5-氟尿嘧啶或 exposure.具体目标2将研究可能 在允许CD 34缺失小鼠存活到成年期中发挥作用， 影响造血表型。具体地说，存在于 正常胸腺已显示支持或抑制造血。我们将 确定CD 34缺失小鼠中的这些胸腺细胞是否提供相同的 功能协调发展的在这个目标中，我们还将研究茎的归巢潜力 细胞移植正常受体， 我们开发了归巢实验，在体内标记干细胞。在 具体目标3将破译CD 34阻断细胞增殖的机制。 造血细胞的分化。我们将鉴定蛋白质， 与细胞内的重要调控结构域相互作用， CD 34分子的区域，其可负控制分化。 我们希望我们的研究结果将直接适用于 治疗血液病、遗传病和恶性肿瘤。

Hematopoietic stem cells are a rare population of cells which have the unique potential to aid cellular therapy for hematological malignancies, bone marrow failure disorders, as well as gene therapy. These cells are most commonly isolated using the CD34 antigen. CD34 is expressed specifically by these cells, but its function is unknown. Whether CD34 function plays a role in stem cell biology is an important question. Furthermore, CD34 expression on the earliest stem cell remains uncertain, although it is well-documented that more mature stem cells express CD34. However, it may be critically important in diseases with stem cell intrinsic defects to use the most primitive stem cell for cellular therapy. Our first specific aim will examine the role for CD34 expression for self-renewal, proliferation, and differentiation of primitive stem cells. This will involve transplantation of CD34 null stem cells into normal mice and normal cells into null mice to test the competence of these null cells. In this setting we will also examine the recovery of endogenous CD34 null stem cells to either radiation of 5-fluorouracil exposure. Specific aim 2 will study the compensatory mechanisms that may be at play in allowing CD34 null mice to survive to adulthood with mildly affected hematopoietic phenotypes. Specifically, cells present in the normal thymus have been shown to support or inhibit hematopoiesis. We will determine if these thymic cells in CD34 null mice provide the same functions. In this aim we will also study the homing potential of stem cells from CD34 null mice to engraft normal recipients using a recently developed homing assay in which we will tag stem cells in vivo. In specific aim 3 will decipher the mechanism by which CD34 blocks the differentiation of hematopoietic cells. We will identify protein(s) which interact with the important regulatory domain within the intracellular region of the CD34 molecule that may negatively control differentiation. We expect that the results of our studies will be directly applicable to treatment of hematological disorders, genetic diseases, and malignancy.