FUNCTION OF CD34 AND ITS ROLE IN STEM CELL BIOLOGY

造血干细胞是一种罕见的具有 独特的潜力，有助于血液系统恶性肿瘤的细胞治疗， 骨髓衰竭疾病，以及基因治疗。这些细胞是 最常见的是使用CD34抗原分离的。CD34的表达 特别是这些细胞，但其功能尚不清楚。CD34是否 功能发挥在干细胞生物学中是一个重要问题。 此外，CD34在最早的干细胞上的表达仍然不确定， 尽管有充分的证据表明，更多的成熟干细胞表达CD34。 然而，它在干细胞疾病中可能是至关重要的。 将最原始的干细胞用于细胞的固有缺陷 心理治疗。我们的第一个具体目标是研究CD34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CD34零干细胞移植到 将正常小鼠和正常小鼠细胞转化为空白小鼠，以检验其能力 这些空单元格。在这种情况下，我们还将检查恢复 内源性CD34缺失干细胞对5-氟尿嘧啶的辐射作用 曝光。具体目标2将研究补偿机制，可能 在允许CD34缺失小鼠存活到成年过程中发挥作用 受影响的造血表型。具体而言，存在于 正常的胸腺已被证明支持或抑制造血。我们会 确定CD34缺失小鼠的这些胸腺细胞是否提供相同的 功能。在这个目标中，我们还将研究茎的归巢潜力 CD34缺失小鼠的细胞移植到正常受者 开发了归巢实验，我们将在体内标记干细胞。在……里面 《特指目标3》将破译CD34阻断 造血细胞的分化。我们将鉴定出哪些蛋白质(S) 与细胞内重要的调控结构域相互作用 CD34分子中可能负向控制分化的区域。 我们预计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.