Myeloid cells in tissue growth and regeneration

骨髓细胞在组织生长和再生中的作用

基本信息

批准号：
9889954
负责人：
LAURA CRISA
金额：
$ 44.13万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-02 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889954
关键词：
Ablation Address Adenosine Adopted Adoptive Transfer Adult Age Aging Anatomy Automobile Driving Biological Models Birth Cell Lineage Cell Proliferation Cell Therapy Cells Cues Degenerative Disorder Development Diabetes Mellitus Disease Duct (organ) structure Embryo Endocrine Epithelial Epithelium Equilibrium Growth Heterogeneity Homeostasis In Vitro Injury Islet Cell Islets of Langerhans Knowledge Lead Life Location Maintenance Mediating Modeling Myelogenous Myeloid Cells Natural Immunity Natural regeneration Organ Pancreas Pancreatic Injury Pathway interactions Pattern Perinatal Phenotype Physiological Population Pregnancy Process Regenerative response Role Signal Pathway Signal Transduction Site Supporting Cell Testing Therapeutic Therapeutic Intervention Tissue Expansion Tissue Model Tissues Work cell type fetal gain of function granulocyte in vivo injury and repair innovation insight islet novel novel therapeutics organ growth pancreatic islet function pathogen progenitor programs recruit regenerative tissue regeneration tissue repair

项目摘要

The ability of tissues to grow to their proper size during development and sustain cell renewal after tissue damage is critical to the maintenance of organ function throughout life. Substantial evidence indicates that loss of tissue resident myeloid cells blunts both physiologic organ’s growth and tissues regenerative potential in aging and after injury. However, the specific myeloid subsets and signaling cues driving such growth effects in different anatomic locations remain unknown. This proposal aims to fill this gap in knowledge by testing the central hypothesis that organ and/or age-specific tissue growth and regenerative potential reflects the recruitment, expansion and/or functional specialization of select myeloid populations. Using the endocrine compartment of the pancreas as a tissue model system endowed with age-restricted proliferative capacity, our previous work identifies CCR2+ myeloid cells as well as granulocytes as regulators of pancreatic islets proliferation in peri-natal life and after injury in vivo. Furthermore, we provide evidence for a role of myeloid-derived adenosine signaling in islet regenerative responses, pointing to myeloid cells as novel targets to convey therapeutic modulation of this pathway to sites of tissue repair. Using this tissue model, we will address our hypothesis in the following aims: 1) Determine the requirement of CCR2+ myeloid cells and granulocytes in islet cell proliferation, using models of myeloid cell subset-specific ablation, adoptive transfer and functional skewing. 2) Determine the functional impact of adenosine signaling on islet proliferation using loss and gain-of function models of this signaling pathway. While providing critical mechanistic insights on the functional diversity of myeloid cells populating tissues during development, homeostasis and regeneration, these studies may lead to novel therapeutic strategies aiming at restoring tissue function following degenerative processes associated with aging and/or injury.

组织在发育过程中生长到适当大小以及在组织损伤后维持细胞更新的能力对于整个生命过程中器官功能的维持至关重要。大量证据表明，组织驻留骨髓细胞的丧失会削弱生理器官的生长和组织再生潜力。然而，在不同解剖位置驱动这种生长效应的特定骨髓亚群和信号线索仍然未知，该提案旨在通过测试器官和/或年龄特异性组织生长和损伤后的中心假设来填补这一知识空白。再生的潜力反映了选定的骨髓细胞群的募集、扩张和/或功能特化，我们之前的工作使用胰腺内分泌室作为具有年龄限制的增殖能力的组织模型系统，确定了 CCR2+ 骨髓细胞以及粒细胞作为骨髓细胞的调节剂。此外，我们还提供了骨髓源性腺苷信号传导在胰岛再生反应中的作用的证据，指出围产期和体内损伤后的胰岛增殖。骨髓细胞作为将该途径的治疗调节传递至组织修复部位的新靶点，利用该组织模型，我们将实现以下目标的假设：1) 使用以下方法确定 CCR2+ 骨髓细胞和粒细胞在胰岛细胞增殖中的需求。骨髓细胞亚群特异性消融、过继转移和功能偏斜的模型 2) 使用该信号通路的功能丧失和获得模型确定腺苷信号传导对胰岛增殖的功能影响。这些研究不仅为组织中的骨髓细胞在发育、稳态和再生过程中的功能多样性提供了重要的机制见解，还可能带来新的治疗策略，旨在恢复与衰老和/或损伤相关的退行性过程后的组织功能。