Mechanisms of G-CSF-Induced Neuroprotection

G-CSF 诱导的神经保护机制

基本信息

批准号：
8288863
负责人：
Jiping Tang
金额：
$ 31.83万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288863
关键词：
Academic Medical Centers Adult Affect Animal Model Apoptosis Apoptotic Basic Science Biochemical Biochemistry Biological Biology Birth Blood - brain barrier anatomy Brain Brain Edema Brain Hypoxia-Ischemia Brain Infarction Brain Injuries Brain-Derived Neurotrophic Factor CSF3 gene Caring Cell Death Cerebral hemisphere hemorrhage Cessation of life Clinical Clinical Sciences Cytotoxic Chemotherapy Data Discipline Doctor of Philosophy Down-Regulation Edema Encephalopathies Environment Family Foundations Goals Granulocyte Colony-Stimulating Factor Granulocyte Colony-Stimulating Factor Receptors Growth Growth Factor Health Healthcare Hematopoietic System Human Hypoxia Hypoxic Brain Damage Immunohistochemistry Infant Intervention Ischemic Brain Injury Janus kinase 2 Label Lead Learning Limb structure Long-Term Effects Measures Mediating Medical Medical center Memory Metabolism Mitochondria Modeling Molecular Morphology Motor Neonatal Neonatal Brain Injury Neonatal Intensive Care Units Nervous System Physiology Neuraxis Neurodevelopmental Disability Neurologic Neurons Neutropenia Outcome Pathway interactions Perinatal Physiology Prevention Proteins Psychology Rattus Reflex action Research Research Personnel Risk Rotarod Performance Test Scientist Sensorimotor functions Sensory Process Signal Pathway Signal Transduction Stat3 protein Stem cells Survivors Testing Therapeutic Time Tissues Transient Cerebral Ischemia Translational Research Traumatic Brain Injury United States United States National Institutes of Health Universities Up-Regulation Water Western Blotting brain tissue cerebral atrophy clinical practice clinically relevant design effective therapy foot improved insight mature animal member natural hypothermia neonatal hypoxic-ischemic brain injury neonate neurobehavioral neuroprotection neurosurgery prevent protective effect research clinical testing socioeconomics translational neuroscience treatment strategy

项目摘要

DESCRIPTION (provided by applicant): No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic (HI) brain damage. Granulocyte-colony stimulating factor (G-CSF), a member of growth factor family, mainly stimulates the proliferation and differentiation of neutrophilic progenitor cells in the hematopoietic system. It has been widely used in clinical practice for the treatment of neutropenia associated with cytotoxic therapy. Recent studies have shown that systemic administration of G-CSF in adult animal models has mediated noteworthy neuroprotective effects in traumatic brain injury, focal transient cerebral ischemia, and intracerebral hemorrhage but its mechanism(s) are not fully elucidated. Whether G-CSF has neuroprotective effects following neonatal hypoxia-ischemia is not known. As a medical scientist and new investigator to the NIH, I have focused on this important question because of its health relevance, nationally and locally. Loma Linda University Medical Center has the largest Neonatal Intensive Care Unit (NICU) in the Western United States. I have bridged basic and clinical science disciplines to assemble an outstanding research team for this project. Our preliminary studies reveal a significant reduction in brain atrophy following systemic administration of G- CSF to an established rat model of neonatal HI and offer insight into mechanism of action. They support our central hypothesis that systemic G-CSF treatment protects the brain against HI-induced apoptosis. To test our main hypothesis, this project is designated to elucidate the impact of G-CSF-mediated neuroprotection on neurobehavioral outcomes, and thereby define its therapeutic potential. Equally important, this project is designed to determine the suppression of cell death mechanisms especially the mitochondrial apoptotic pathways that mediates the protective effects of G-CSF. The neuroprotective effects of G-CSF on neuronal death and brain atrophy will be related to neurobehavioral outcomes (Specific Aim 1). Brain damage will be measured by brain tissue loss, edema formation, blood-brain barrier disruption, brain infarction, and cellular morphological changes. To strengthen the clinical relevance of this project, the long-term effect and mechanisms of G-CSF treatment on sensorimotor functions, memory and learning abilities will be evaluated by a battery of neurological tests. Then G-CSF's underlying mechanism will be investigated in greater depth by measuring its effect on HI-induced activation of signaling pathways especially mitochondrial apoptotic pathways (Specific Aim 2). The apoptotic changes will be studied using biochemical and molecular approaches. Achieving our project goal through these specific aims will lay the foundation for clinical evaluation of systemic G-CSF in NICU neonates for prevention and treatment of brain damage from HI. PUBLIC HEALTH RELEVANCE: No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic brain damage. Our project goal is to relate G-CSF's protection of neonates from hypoxia/ischemia-induced brain damage to both neurological function and underlying mechanism. Achieving our goal will lay the foundation for clinical evaluation of systemic administration of G-CSF in human neonates for prevention and treatment of brain damage from hypoxia/ischemia.

描述（由申请人提供）：尚未开发出有效的治疗策略来预防或减少新生儿缺氧/缺血（HI）脑损伤。粒细胞集落刺激因子（G-CSF）属于生长因子家族成员，主要刺激造血系统中性粒细胞祖细胞的增殖和分化。它已广泛应用于临床实践中，用于治疗与细胞毒疗法相关的中性粒细胞减少症。最近的研究表明，在成年动物模型中全身施用G-CSF对创伤性脑损伤、局灶性短暂性脑缺血和脑出血具有显着的神经保护作用，但其机制尚未完全阐明。 G-CSF 是否对新生儿缺氧缺血后具有神经保护作用尚不清楚。作为一名医学科学家和美国国立卫生研究院的新研究员，我一直关注这个重要问题，因为它与国家和地方的健康相关。洛马琳达大学医学中心拥有美国西部最大的新生儿重症监护病房 (NICU)。我将基础科学和临床科学学科联系起来，为这个项目组建了一支优秀的研究团队。我们的初步研究表明，对已建立的新生儿 HI 大鼠模型全身施用 G-CSF 后，脑萎缩显着减少，并提供了对作用机制的深入了解。它们支持我们的中心假设，即全身 G-CSF 治疗可保护大脑免受 HI 诱导的细胞凋亡。为了检验我们的主要假设，该项目旨在阐明 G-CSF 介导的神经保护对神经行为结果的影响，从而确定其治疗潜力。同样重要的是，该项目旨在确定细胞死亡机制的抑制，特别是介导 G-CSF 保护作用的线粒体凋亡途径。 G-CSF 对神经元死亡和脑萎缩的神经保护作用将与神经行为结果相关（具体目标 1）。脑损伤可通过脑组织损失、水肿形成、血脑屏障破坏、脑梗塞和细胞形态变化来衡量。为了加强该项目的临床相关性，将通过一系列神经学测试来评估 G-CSF 治疗对感觉运动功能、记忆和学习能力的长期效果和机制。然后，通过测量 G-CSF 对 HI 诱导的信号通路特别是线粒体凋亡通路激活的影响，将更深入地研究 G-CSF 的潜在机制（具体目标 2）。将使用生化和分子方法研究细胞凋亡的变化。通过这些具体目标实现我们的项目目标将为 NICU 新生儿全身性 G-CSF 预防和治疗 HI 脑损伤的临床评估奠定基础。公共卫生相关性：尚未开发出有效的治疗策略来预防或减少新生儿缺氧/缺血性脑损伤。我们的项目目标是将 G-CSF 对新生儿免受缺氧/缺血引起的脑损伤的保护与神经功能和潜在机制联系起来。实现我们的目标将为人类新生儿全身施用G-CSF预防和治疗缺氧/缺血引起的脑损伤的临床评估奠定基础。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.

促红细胞生成素通过缺氧缺血体外模型中 PHD-2 转录和翻译的上调抑制 HIF-1α 表达。

DOI：
发表时间：
2014-02
期刊：
影响因子：
6.9
作者：
Souvenir, Rhonda;Flores, Jerry J;Ostrowski, Robert P;Manaenko, Anatol;Duris, Kamil;Tang, Jiping
通讯作者：
Tang, Jiping

Granulocyte-colony stimulating factor activates JAK2/PI3K/PDE3B pathway to inhibit corticosterone synthesis in a neonatal hypoxic-ischemic brain injury rat model.

粒细胞集落刺激因子激活 JAK2/PI3K/PDE3B 通路抑制新生缺氧缺血性脑损伤大鼠模型中皮质酮的合成。

DOI：
发表时间：
2015-10
期刊：
影响因子：
5.3
作者：
Charles, Mélissa S;Drunalini Perera, Pradilka N;Doycheva, Desislava Met;Tang, Jiping
通讯作者：
Tang, Jiping

Anti-neutrophil antibody enhances the neuroprotective effects of G-CSF by decreasing number of neutrophils in hypoxic ischemic neonatal rat model.

抗中性粒细胞抗体通过减少缺氧缺血新生大鼠模型中的中性粒细胞数量来增强 G-CSF 的神经保护作用。

DOI：
发表时间：
2014-09
期刊：
影响因子：
6.1
作者：
Doycheva, Desislava M;Hadley, Tiffany;Li, Li;Applegate 2nd, Richard L;Zhang, John H;Tang, Jiping
通讯作者：
Tang, Jiping

Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway.

远程肢体缺血后处理可通过阿片受体/Akt 通路保护幼鼠免受新生儿缺氧缺血性脑损伤。

DOI：
发表时间：
2011-02
期刊：
影响因子：
0
作者：
Zhou, Yilin;Fathali, Nancy;Lekic, Tim;Ostrowski, Robert P;Chen, Chunhua;Martin, Robert D;Tang, Jiping;Zhang, John H
通讯作者：
Zhang, John H

Comparison Evans Blue injection routes: Intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model.

比较伊文思蓝注射途径：静脉注射与腹膜内注射，用于测量小鼠出血模型中的血脑屏障。