Development of an animal model to test HDAC6 as a drug target to reduce and/or prevent fetal growth restriction

开发动物模型来测试 HDAC6 作为减少和/或预防胎儿生长受限的药物靶点

基本信息

批准号：
10785825
负责人：
Amy N Abell
金额：
$ 13.85万
依托单位：
UNIVERSITY OF MEMPHIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785825
关键词：
Active Biological Transport Adult Affect Alzheimer&apos s Disease Animal Model Automobile Driving Backcrossings Cells Clinical Trials Data Development Drug Targeting Embryo Enzymes Essential Amino Acids Failure Family member Female Fetal Development Fetal Growth Fetal Growth Retardation Fetus Fibrosis Frequencies Generations Glucose Goals Growth HDAC6 gene Health Heterozygote Histone Deacetylase Histone Deacetylase Inhibitor Hormones Human Hyperactivity Hypertension Individual Insulin Receptor Insulin-Like-Growth Factor I Receptor Knockout Mice MAP3K4 gene MAP4K4 gene Measures Methods Molecular Morbidity - disease rate Mus Mutation Neonatal Neonatal Mortality Nutrient Oxygen Partner in relationship Pathology Perinatal mortality demographics Phosphorylation Phosphotransferases Placenta Placental Insufficiency Pregnancy Premature Birth Prevention Process Publishing Research Role Scanning Speed Spontaneous abortion Testing Therapeutic Therapeutic Intervention Transcript Weaning Work animal model development chondrodysplasia fetal improved inhibitor knock-down mortality mouse model neonatal morbidity novel strategies novel therapeutics overexpression pregnant prenatal therapy prevent protein expression receptor receptor expression small molecule success therapeutic target timeline tool trophoblast trophoblast stem cell

Active Biological Transport Adult Affect Alzheimer&apos s Disease Animal Model Automobile Driving Backcrossings Cells Clinical Trials Data Development Drug Targeting Embryo Enzymes Essential Amino Acids Failure Family member Female Fetal Development Fetal Growth Fetal Growth Retardation Fetus Fibrosis Frequencies Generations Glucose Goals Growth HDAC6 gene Health Heterozygote Histone Deacetylase Histone Deacetylase Inhibitor Hormones Human Hyperactivity Hypertension Individual Insulin Receptor Insulin-Like-Growth Factor I Receptor Knockout Mice MAP3K4 gene MAP4K4 gene Measures Methods Molecular Morbidity - disease rate Mus Mutation Neonatal Neonatal Mortality Nutrient Oxygen Partner in relationship Pathology Perinatal mortality demographics Phosphorylation Phosphotransferases Placenta Placental Insufficiency Pregnancy Premature Birth Prevention Process Publishing Research Role Scanning Speed Spontaneous abortion Testing Therapeutic Therapeutic Intervention Transcript Weaning Work animal model development chondrodysplasia fetal improved inhibitor knock-down mortality mouse model neonatal morbidity novel strategies novel therapeutics overexpression pregnant prenatal therapy prevent protein expression receptor receptor expression small molecule success therapeutic target timeline tool trophoblast trophoblast stem cell

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项目摘要

PROJECT SUMMARY Disruption of fetal growth results in severe consequences to human health, including increased fetal and neonatal morbidity and mortality, as well as potential lifelong health problems. Fetal growth restriction (FGR) occurs in up to 10% of all human pregnancies. Unfortunately, treatments for FGR are lacking. Molecular mechanisms promoting fetal growth represent potential therapeutic strategies to treat and/or prevent FGR. We have identified a previously unknown role for the mitogen activated protein kinase kinase kinase 4 (MAP3K4) in promoting fetal and placental growth by inducing the expression and activity of the insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (IR). In recent work published in 2022, we discovered that inactivation of MAP3K4 kinase activity by a mutation in the kinase domain results in FGR. MAP3K4 Kinase-Inactive (KI) mice display high lethality prior to weaning and persistent growth reduction of surviving adults. Expression and activation of the IGF1R and IR are reduced in both cultured KI trophoblasts and KI placentas. Mechanism(s) by which MAP3K4 controls these receptors represent novel approaches to treat FGR. MAP3K4 inhibits the expression and activity of histone deacetylase 6 (HDAC6). KI trophoblasts have elevated HDAC6 expression and activity, and reduction of HDAC6 restores IGF1R and IR expression and activity. Based on these findings, we hypothesize that HDAC6 may also be hyperactive in KI placentas, and HDAC6 inhibition may rescue and prevent FGR. The availability of highly selective and well-tolerated HDAC6 inhibitors provides a unique opportunity for developing a therapy to treat FGR. However, it remains unknown if targeting HDAC6 during pregnancy will improve fetal and placental growth. Our preliminary data show that inhibition of HDAC6 during pregnancy increased the survival of KI embryos during development. However, this rescue may be due in part to off target effects of HDAC6 inhibitors. To test our prediction that deletion of HDAC6 will prevent FGR in KI mice, we propose to genetically delete HDAC6 from MAP3K4 KI mice by mating them with HDAC6 knockout mice. Survival and growth of MAP3K4 KI mice lacking HDAC6 will be assessed. In addition, fetal and placental size will be measured, and placental expression and activity of the IGF1R, IR, and Akt will be quantified. These new results will be compared to growth restriction and lethality observed in the presence of elevated HDAC6. We predict that deletion of HDAC6 from MAP3K4 KI individuals will improve fetal growth and increase survival, indicating that HDAC6 inhibitors may represent a new therapeutic tool to treat FGR.

项目摘要胎儿生长的破坏会对人类健康造成严重后果，包括胎儿增加和新生儿发病率和死亡率以及潜在的终身健康问题。胎儿生长限制（FGR）最多发生在所有人类怀孕中的10％。不幸的是，缺乏对FGR的治疗方法。分子促进胎儿生长的机制代表了治疗和/或预防FGR的潜在治疗策略。我们已经确定了有丝分裂激活的蛋白激酶激酶激酶4（MAP3K4）的先前未知作用通过诱导胰岛素样生长因子的表达和活性来促进胎儿和胎盘生长 1受体（IGF1R）和胰岛素受体（IR）。在2022年发表的最新作品中，我们发现这种失活通过激酶结构域突变的MAP3K4激酶活性导致FGR。 MAP3K4激酶 - 活性（KI）在断奶和持续的成年人持续增长之前，小鼠表现出很高的致死性。表达和在培养的Ki滋养细胞和Ki胎盘中，IGF1R和IR的激活均降低。机理 MAP3K4控制这些受体代表了治疗FGR的新方法。 map3k4抑制组蛋白脱乙酰基酶6（HDAC6）的表达和活性。 Ki滋养细胞的HDAC6表达升高 HDAC6的活性以及降低恢复IGF1R以及IR表达和活性。基于这些发现，我们假设HDAC6在Ki胎盘中也可能充分活跃，HDAC6抑制可能会营救，并且防止FGR。高度选择性和耐受性良好的HDAC6抑制剂的可用性提供了独特的开发治疗FGR的疗法的机会。但是，在靶向HDAC6时，尚不清楚怀孕将改善胎儿和胎盘生长。我们的初步数据表明，抑制HDAC6在妊娠在发育过程中增加了Ki胚胎的存活。但是，此救援可能部分到期关闭HDAC6抑制剂的靶向效应。为了测试我们的预测，HDAC6的删除将阻止Ki中的FGR 小鼠，我们建议通过将它们与HDAC6敲除从MAP3K4 Ki小鼠中删除HDAC6 老鼠。将评估缺乏HDAC6的MAP3K4 Ki小鼠的生存和生长。另外，胎儿和胎盘将测量大小，并将量化IGF1R，IR和AKT的胎盘表达和活性。这些在HDAC6升高的情况下，将将新结果与生长限制和致死性进行比较。我们预测，从map3k4 ki个体中删除HDAC6将改善胎儿的生长并提高生存率，表明HDAC6抑制剂可能代表一种治疗FGR的新治疗工具。