Axolotl Hematopoiesis: A Regeneration Model

蝾螈造血：再生模型

• 批准号: 8915413
• 负责人: Edward W Scott
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915413
• 关键词: Acomys; Active Sites; Adult; African; Ambystoma; Ambystoma mexicanum; Amphibia; Animals; Antibodies; Benign; Biological Metamorphosis; Biological Models; Biology; Blood; Blood Cells; Brain; Breeding; Cancer Biology; Carcinogens; Cartilage; Cell Transplants; Cell surface; Cells; Chimera organism; Cicatrix; Colony-Forming Units Assay; Color; Comparative Study; Competence; Complex; Cytomegalovirus; Development; Embryo; Engraftment; Equilibrium; Genetic; Genetic Models; Goals; Grant; Growth; Healed; Heart; Hematopoiesis; Hematopoietic; Hematopoietic System; Homing; Imagery; Immune; Immune system; Immunity; Inflammation; Jaw; Knowledge; Leukocyte Elastase; Leukocytes; Limb structure; Liver; MYB gene; Malignant Neoplasms; Mammals; Maps; Methodology; Microsurgery; Modeling; Morphology; Muramidase; Mus; Muscle; Mutagens; Myelogenous; Myelopoiesis; Natural regeneration; Neoplasms; Organ; Paper; Pathway interactions; Patients; Peroxidases; Play; Proto-Oncogene Proteins c-myb; PubMed; Publishing; Rana; Reagent; Regulation; Relative (related person); Reporter; Reptiles; Research; Role; S100A8 gene; Salamander; Site; Skin; Skin Tissue; Spinal Cord; Spleen; Structure; Tail; Techniques; Testing; Time; Tissues; Transgenic Organisms; Vertebrates; Wound Healing; Zebrafish; carcinogenesis; comparative; design; healing; immune clearance; improved; in vivo; limb regeneration; macrophage; mouse model; mutant; neutrophil; paracrine; progenitor; promoter; public health relevance; reconstitution; regenerative; segregation; tissue regeneration; trait; tumorigenesis; Acomys; Active Sites; Adult; African; Ambystoma; Ambystoma mexicanum; Amphibia; Animals; Antibodies; Benign; Biological Metamorphosis; Biological Models; Biology; Blood; Blood Cells; Brain; Breeding; Cancer Biology; Carcinogens; Cartilage; Cell Transplants; Cell surface; Cells; Chimera organism; Cicatrix; Colony-Forming Units Assay; Color; Comparative Study; Competence; Complex; Cytomegalovirus; Development; Embryo; Engraftment; Equilibrium; Genetic; Genetic Models; Goals; Grant; Growth; Healed; Heart; Hematopoiesis; Hematopoietic; Hematopoietic System; Homing; Imagery; Immune; Immune system; Immunity; Inflammation; Jaw; Knowledge; Leukocyte Elastase; Leukocytes; Limb structure; Liver; MYB gene; Malignant Neoplasms; Mammals; Maps; Methodology; Microsurgery; Modeling; Morphology; Muramidase; Mus; Muscle; Mutagens; Myelogenous; Myelopoiesis; Natural regeneration; Neoplasms; Organ; Paper; Pathway interactions; Patients; Peroxidases; Play; Proto-Oncogene Proteins c-myb; PubMed; Publishing; Rana; Reagent; Regulation; Relative (related person); Reporter; Reptiles; Research; Role; S100A8 gene; Salamander; Site; Skin; Skin Tissue; Spinal Cord; Spleen; Structure; Tail; Techniques; Testing; Time; Tissues; Transgenic Organisms; Vertebrates; Wound Healing; Zebrafish; carcinogenesis; comparative; design; healing; immune clearance; improved; in vivo; limb regeneration; macrophage; mouse model; mutant; neutrophil; paracrine; progenitor; promoter; public health relevance; reconstitution; regenerative; segregation; tissue regeneration; trait; tumorigenesis

 DESCRIPTION (provided by applicant): In mammals, the ability to regenerate limbs and organs is progressively lost during ontogeny and correlates closely with maturation of immune competence. Research in scar-free wound healing, primarily observed in model systems with dysfunctional neutrophils and macrophages, has led to the hypothesis that the immune system dictates the balance between scarring and regeneration. We seek to test this hypothesis by studying a regenerative animal. Among vertebrates, urodele amphibians, such as the axolotl (Ambystoma mexicanum), display a unique and extensive ability for adult regeneration. Axolotls can replace a wide variety of tissues and complex structures including muscle, cartilage, skin, spinal cord, brain, heart, jaw, and limbs. Axolotl also do not get cancer. Mutagens do not induce transformation in axolotls at worst they induce spurious regeneration or a small benign neoplasia. Enhanced immune clearance of damaged tissue by axolotl leukocytes is another hypothesis we hope to test. To do so, we must better define the axolotl hematopoietic system - particularly the myeloid lineages where very little beyond morphology is known. Defining the genetic pathways required in the hematopoietic system for regeneration via a comparative approach contrasting matched murine and axolotl wound healing/regeneration models is one long-term goal that will be facilitated by these studies. These studies will also facilitate definig the role of hematopoietic cells in axolotl cancer immunity by similar comparative approaches replicating well establishes murine models of oncogenesis in axolotl. This proposal seeks to provide the initial characterization of axolotl hematopoietic ontogeny with a focus on myeloid development. A PubMed search for axolotl HSC, macrophages, or neutrophils yields fewer than 25 relevant papers published since 1972. Therefore, the design of this proposal is more empirical using tested methodology from mammalian and zebrafish studies to delineate axolotl hematopoiesis/myelopoiesis. Heavy emphasis will be placed on identifying/generating antibody reagents for hematopoietic specific cell surface markers. In addition, we will use previously successful hematopoietic specific transgenic reporter constructs (Vav-1, gata-1, PU.1 (made myself)), c-myb, Lyz (lysozyme), MRP8 (mac specific), Mpx (myeloperoxidase) and NE (neutrophil elastase) regulatory/promoter constructs) to generate matching axolotl transgenic strains to facilitate comparative studies. We have two Specific Aims: Aim 1. Defining the Axolotl HSC: Ontogeny, Function and Niche. Aim2. Characterization of Macrophages and Neutrophils in Axolotl.

 描述（由适用提供）：在哺乳动物中，在本体发育过程中逐渐丢失了肢体和器官的能力，并且与免疫能力成熟密切相关。无疤痕伤口愈合的研究主要在具有功能失调的中性粒细胞和巨噬细胞的模型系统中观察到，这导致了这样的假设，即免疫系统决定了疤痕和再生之间的平衡。我们试图通过研究再生动物来检验这一假设。在脊椎动物中，尿毒症两栖动物（例如Ambystoma Mexicanum）具有独特而广泛的成人再生能力。 Axolotls可以取代各种组织和复杂的结构，包括肌肉，软骨，皮肤，脊髓，大脑，心脏，下颌和四肢。 Axolotl也没有癌症。在最坏的情况下，诱变剂不会诱导axolotls的转化，它们会诱导虚假再生或小的良性肿瘤。通过Axolotl白细胞增强了损坏的组织的免疫缓解，我们希望测试的另一个假设。为此，我们必须更好地定义Axolotl造血系统 - 尤其是髓样谱系，而超出形态的众所周知。通过比较方法对比匹配的鼠和Axolotl伤口愈合/再生模型来定义造血系统中所需的遗传途径是一个长期目标，这些目标将促进这些研究的促进。这些研究还将通过类似的比较方法复制良好的比较方法来促进造血细胞在Axolotl癌症免疫中的作用，从而在Axolotl中建立了鼠类发生的鼠模型。该提案旨在提供Axolotl造血个体发育的初始特征，重点是髓样发育。自1972年以来，对Axolotl HSC，巨噬细胞或中性粒细胞的PubMed搜索产生的相关论文少于25个相关论文。因此，使用哺乳动物和斑马鱼研究的测试方法，该提案的设计更具经验性，以划定Axolotl habatopoiesis/merelopiesis。重点将放在识别/生成造血特异性细胞表面标记的抗体试剂上。 In addition, we will use previously successful hematopoietic specific transgenic reporter constructs (Vav-1, gata-1, PU.1 (made) myself)), c-myb, Lyz (lysozyme), MRP8 (mac specific), Mpx (myeloperoxidase) and NE (neutrophil elastase) regulatory/promoter constructs) to generate matching axolotl transgenic strains to facilitate comparative研究。我们有两个具体的目标：目标1。定义Axolotl HSC：个体发育，功能和利基市场。 AIM2。巨噬细胞和嗜中性粒细胞的表征。