Mechanisms of Hematopoiesis in AIDS

艾滋病的造血机制

• 批准号: 7903316
• 负责人: David T Scadden
• 金额: $ 52.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903316
• 关键词: Acquired Immunodeficiency Syndrome; Bone Marrow; Calcium-Sensing Receptors; Cell Therapy; Cell physiology; Clinical; Clinical Trials; Development; Drug Delivery Systems; Endosteum; Engraftment; Gene-Modified; Goals; Grant; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Lead; Malignant Neoplasms; Molecular; Nature; Osteoblasts; Outcome; Pharmaceutical Preparations; Pre-Clinical Model; Role; Specific qualifier value; Stem cell transplant; Stem cells; Surface; Testing; Translating; Transplantation; clinical application; improved; in vivo; stem cell niche; stem cell therapy

DESCRIPTION (provided by applicant): Mechanisms of Hematopoiesis in AIDS - The goal of this proposal is to improve the efficiency of stem cell engraftment in stem cell based therapies. It uses a recently defined molecular determinant of hematopoietic stem cell localization to define the specific role of the bone marrow endosteal niche and to develop practical strategies for enhancing stem cell engagement of it. Results from the prior grant period demonstrated that osteoblasts on the endosteal surface were a critical regulator of stem cell function and could be targeted to alter outcomes of stem cell transplantation in vivo. These results have resulted in ongoing clinical trials. Results of the prior grant period also resulted in demonstration that the calcium sensing receptor (CaR) on stem cells specifies the engraftment of stem cells at the endosteal niche in development and transplantation. The current proposal seeks to extend these studies to both understand in greater depth the specific functions of specific stem cell niches in vivo and test pre-clinical models for targeting the stem cell calcium sensing receptor therapeutically. Since drugs targeting CaR are already in clinical use for other indications, the studies proposed here have the potential of rapidly translating to clinical application by re-purposing existing medications. The specific aims of this proposal are: 1: Exploit the endosteum specifying action of stem cell CaR to define specific functions of the endosteal niche compared with other stem cell niches 2: Modify CaR activity or expression to change stem cell localization and function in settings of clinical importance. These studies are intended to facilitate stem cell therapies through both basic and applied analyses. If successful, they will lead to increased engraftment efficiency of stem cells, a parameter critical for advancing stem cell therapies in blood diseases and cancer, including gene modified stem cells for AIDS.

描述（由申请人提供）：艾滋病中造血的机制 - 该提案的目的是提高干细胞植入基于干细胞的疗法的效率。它使用最近定义的造血干细胞定位的分子决定因素来定义骨髓内脊髓生态位的特定作用，并制定了增强其干细胞参与的实用策略。上一批赠款期的结果表明，内骨表面上的成骨细胞是干细胞功能的关键调节剂，可以针对改变体内干细胞移植的结果。 这些结果导致了正在进行的临床试验。上一批赠款期的结果还导致证明了干细胞上的钙传感受体（CAR）指定在发育和移植中内层小裂中干细胞的植入。 当前的建议旨在扩展这些研究，以更深入地了解体内特定干细胞壁细胞的特定功能，以及用于靶向干细胞钙感应受体治疗的临床前模型。由于靶向汽车的药物已经用于其他适应症的临床用途，因此此处提出的研究有可能通过重新定位现有药物来快速转化为临床应用。该提案的具体目的是：1：利用内接托管指定干细胞汽车的作用，以定义内接和壁che的特定功能，与其他干细胞壁细分2：修改CAR活性或表达以改变干细胞的定位和在临床重要性的设置中的功能。这些研究旨在通过基本和应用分析来促进干细胞疗法。如果成功的话，它们将导致干细胞的植入效率提高，这对于推进血液疾病和癌症的干细胞疗法至关重要的参数，包括艾滋病基因修饰的干细胞。