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Development of a Neuroprotective Agent For Cerebral Palsy Prevention

开发用于预防脑瘫的神经保护剂

基本信息

批准号：
8714223
负责人：
Rafael Galindo
金额：
$ 15.04万
依托单位：
ZIETCHICK RESEARCH INSTITUTE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714223
关键词：
Adopted Adverse effects Affect American Animals Apoptosis Apoptotic Applications Grants Area Asians Asphyxia Asphyxia Neonatorum Behavioral Behavioral Paradigm Biological Sciences Birth Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Cerebral Palsy Cerebral cortex Cessation of life Child Childhood Clinical Clinical Trials Cognitive deficits Collaborations Control Groups Corpus striatum structure Development Effectiveness Encephalopathies Epidemiology Epilepsy Family Female Fetus Frequencies Functional disorder Goals Hippocampus (Brain)Hormone Receptor Hormones Human Human Chorionic Gonadotropin Hypoxia Impaired cognition In Vitro Infant Injury Intellectual functioning disability Ischemic-Hypoxic Encephalopathy LH Receptors Language Lead Life Magnesium Sulfate Measurement Measures Methods Mothers Motor Mus Neonatal Neurologic Neurons Neuroprotective Agents Newborn Infant Nutritional Outcome Pathway interactions Patients Perinatal Pharmaceutical Preparations Phase Play Pregnancy Premature Infant Prevention Process Regimen Research Institute Risk Risk Factors Role Safety Saline Severities Small Business Technology Transfer Research Supplementation Testing Time Tissues Translating Universities Washington Woman Women&apos s Group adverse outcome brain tissue caspase-3 design disability disorder prevention dosage fetal hypoxia neonatorum in utero intraperitoneal motor deficit mouse model neonatal hypoxic-ischemic brain injury neonate neurobehavioral neuron loss neuroprotection novel offspring pre-clinical prevent protective effect public health relevance pup research clinical testing research study response

项目摘要

DESCRIPTION (provided by applicant): Cerebral palsy (CP), the most common physical disability in childhood, afflicts more than 800,000 Americans and many more worldwide. In addition to motor difficulties, many children with CP also suffer from intellectual disability, epilepsy, nutritional problems, and language dysfunction. Furthermore, almost 90% of CP-associated brain injuries occur in utero or around the time of birth. Therefore, a medication to prevent CP needs to be able to be safely administered either during pregnancy to the mom and/or shortly after birth to the neonate. The goal of this Phase I grant proposal is to demonstrate the feasibility that a naturally-occurring hormone can be developed into a medicament for CP prevention. There is already evidence supporting the role of this hormone as a neuroprotective agent against CP; receptors for this hormone are expressed in the developing brain, and administration of this hormone has been shown to decrease neuronal cell death, promote the proliferation of developing neurons and the outgrowth of neuronal processes in vitro. Furthermore, we have identified epidemiological evidence of an inverse relationship between CP risk and mean maternal levels of this hormone; offspring from nine epidemiologically distinct groups of women who have higher mean levels of this hormone during pregnancy have a lower CP risk. During Phase I, the capability of this hormone to induce neuroprotection will be investigated in a neonatal mouse model that produces neurological deficits similar to those seen in CP (i.e. pups who have been subjected to term-equivalent hypoxic-ischemic brain injury). Utilizing conventional histochemical methods, the amount of brain tissue loss in a hormone-injected group of neonatal mice will be compared to a control group 7 days after both groups have been subjected to the hypoxia-ischemia regimen. In addition, caspase-3 activation, a quantifiable measure of the extent of apoptotic neuronal cell death in response to neonatal hypoxic-ischemic injury, will be compared between groups. Lastly, the neurobehavioral outcome in the experimental and control groups will be examined utilizing established animal behavioral paradigms. In Phase II, we will refine the concentration, timing and frequency of hCG dosage and perform all preclinical hCG safety experiments to prepare for clinical testing.

描述（由申请人提供）：脑瘫（CP）是儿童时期最常见的身体残疾，困扰着80多万美国人和世界各地的许多人。除了运动困难外，许多CP儿童还患有智力障碍、癫痫、营养问题和语言障碍。此外，几乎90%的CP相关脑损伤发生在子宫内或出生时。因此，预防CP的药物需要能够在怀孕期间安全地施用给母亲和/或在出生后不久安全地施用给新生儿。这个第一阶段拨款提案的目标是证明一种天然激素可以开发成预防CP的药物的可行性。已经有证据支持这种激素作为抗CP的神经保护剂的作用;这种激素的受体在发育中的大脑中表达，并且这种激素的施用已经显示出减少神经元细胞死亡，促进发育中的神经元的增殖和体外神经元过程的生长。此外，我们已经确定了流行病学的证据，CP风险和平均产妇水平的这种激素之间的负相关关系，从9个流行病学不同的妇女群体的后代在怀孕期间有较高的平均水平的这种激素有较低的CP风险。在第I阶段，将在新生小鼠模型中研究该激素诱导神经保护的能力，该模型产生与CP中观察到的神经功能缺损相似的神经功能缺损（即，遭受足月等效缺氧缺血性脑损伤的幼仔）。使用常规组织化学方法，在两组都经历缺氧-缺血方案后7天，将注射过维生素E的新生小鼠组中的脑组织损失量与对照组进行比较。此外，还将比较两组之间的半胱天冬酶-3活化，这是新生儿缺氧缺血性损伤引起的神经元细胞凋亡程度的一种可量化指标。最后，将利用已建立的动物行为范例检查实验组和对照组的神经行为结果。在第二阶段，我们将完善hCG给药的浓度、时间和频率，并进行所有临床前hCG安全性实验，为临床试验做准备。