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Therapeutic agents to prevent developmental neuroimpairment after placental hormone loss

预防胎盘激素丢失后发育性神经损伤的治疗药物

基本信息

批准号：
10510450
负责人：
ANNA A PENN
金额：
$ 24.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510450
关键词：
Acute Address Adverse effects Age Allopregnanolone Anatomy Area Behavior Behavioral Biological Markers Birth Birth Place Brain Brain Injuries Cerebellum Clinical Complex Cre-LoxP Development Disease Dose Drug Delivery Systems Embryo Endocrine Endocrine Glands Engineering Enzymes Exhibits Exposure to FOS gene Female Functional disorder GABA Agents GABA-A Receptor Genes Goals Half-Life Hormones Human Impairment Infant Investigation Knowledge Life Link Modeling Mus Myelin Basic Proteins Nature Neurodevelopmental Deficit Neurodevelopmental Disorder Neurodevelopmental Impairment Neurologic Neurosciences Newborn Infant Outcome Pathway interactions Perinatal Pharmacological Treatment Pharmacotherapy Phase II/III Trial Placenta Placental Hormones Pregnancy Premature Birth Premature Infant Production Progesterone Property Repair Complex Reporting Rest Risk Risk Factors Role Safety Synapses Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Work analog autism spectrum disorder behavior test brain dysfunction cell type cellular targeting experimental study fetal ganaxolone high risk human male improved insight male molecular marker mouse model myelination neurobehavioral neuroprotection neurosteroids novel offspring postnatal pre-clinical pregnant prenatal prevent protein biomarkers protein expression public health relevance repetitive behavior response sex social cognition white matter

项目摘要

PROJECT SUMMARY/ABSTRACT Premature birth results in early loss of the key endocrine organ of pregnancy, the placenta. Placental endocrine dysfunction or loss may place many thousands of infants at risk of life-long neurodevelopmental impairment each year. We have begun to define the placental hormone contribution to neurodevelopmental disorders, such as autism spectrum disorders (ASD) in a novel mouse model. Reducing a single placental hormone, allopregnanolone (ALLO), in late gestation produces specific long-term neurodevelopmental deficits that mimic those seen in preterm birth and ASD. ALLO is a neuroactive steroid synthesized from progesterone by the placenta during late gestation. It acts on the brain through allosteric activation of GABA-A receptor (GABAAR); its loss can alter the GABAergic milieu that is critical for normal development. Decreased placental ALLO leads to alterations in postnatal cerebellar myelination and ASD-like behaviors in a sex-linked manner, with males showing increased myelination, females a decrease and only males exhibiting ASD-like features including social cognition deficits and increased repetitive behavior. Both our mouse model and human preterm male cerebellum showed increased Myelin Basic Protein (MBP) and other protein markers of myelination that, in mice, correlated with ASD-like behavior. A single ALLO dose injected into pregnant Cre-Lox dams in late gestation rescued the cerebellar MBP abnormalities and ASD-like behaviors in male plKO mice. These findings support our overall hypothesis that altered cerebellar white matter development and ASD-like behaviors seen in male offspring exposed to reduced placental ALLO is amenable to pharmacological treatment. These initial rescue experiments are promising and we have found a rescue paradigm that works, but there are still critical knowledge gaps that must be addressed. Here we will test ALLO and two of its engineered derivatives—ganaxolone (GAN), which has a longer half-life, and gaboxadol (GAB), which activates primarily extrasynaptic rather than synaptic GABAARs-- all of which have shown good human safety profiles in phase II/III trials for other indications. We will compare the ability of exogenous ALLO versus its analogues to rescue the complex neurobehavioral effects of placental hormone loss (Aim 1) and determine the effects of perinatal timing of administration of ALLO or one of its derivatives (Aim 2) on degree of neurological rescue after placental hormone loss. These agents will be assessed in our new mouse model using cerebellar MBP expression as an initial biomarker and neurobehavioral normalization as the relevant therapeutic goal. Accomplishing these aims will provide new mechanistic insights into the necessary properties of GABAergic agents that best rescue loss of a key placental hormone and take a practical step towards development of new treatments to prevent or repair the complex neurodevelopmental sequelae of placental loss.

项目总结/文摘