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.

在组织损害后，尖端在发育过程中成长到适当的大小和维持细胞更新的能力对于维持器官功能的维持至关重要。大量证据表明，组织居民骨髓细胞的丧失均钝化生理器官的生长和尖端在衰老和损伤后的再生潜力。但是，在不同解剖位置驱动这种生长效应的特定髓样子集和信号提示仍然未知。该提案旨在通过测试中心假设来填补这一空白，即器官和/或特定年龄的组织生长和再生潜力反映了某些髓样群体的募集，扩展和/或功能专业化。我们以前的工作使用胰腺的内分泌室作为组织模型系统，它以年龄限制的增殖能力为生，将CCR2+髓样细胞和粒细胞鉴定为胰岛增殖的调节剂，以在肿瘤周期寿命和受伤后的体内受伤。此外，我们为胰岛再生反应中的髓样衍生的腺苷信号传导的作用提供了证据，指出髓样细胞是传达该途径到组织修复部位的治疗调节的新靶标。使用该组织模型，我们将在以下目的中解决我们的假设：1）使用髓样细胞特异性消融，自适应转移和功能偏斜的模型，确定胰岛细胞增殖中CCR2+髓细胞和粒细胞的需求。 2）使用此信号通路的损失和功能模型来确定腺苷信号传导对胰岛增殖的功能影响。在对在发育，稳态和再生过程中填充组织的功能多样性的关键机械见解的同时，这些研究可能导致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。