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

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.

项目概要胎儿生长的破坏会对人类健康造成严重后果，包括增加胎儿和新生儿发病率和死亡率，以及潜在的终身健康问题。胎儿生长受限（FGR）高达 10% 的人类妊娠发生这种情况。不幸的是，目前缺乏针对 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。我们已经确定了丝裂原激活蛋白激酶激酶 4 (MAP3K4) 的先前未知的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 年发表的最新研究中，我们发现失活 MAP3K4 激酶活性因激酶结构域突变而降低，导致 FGR。 MAP3K4 激酶失活 (KI) 小鼠在断奶前表现出高致死率，并且存活的成年小鼠的生长持续减少。表达和在培养的 KI 滋养层和 KI 胎盘中，IGF1R 和 IR 的激活均减少。机制由 MAP3K4 控制这些受体代表了治疗 FGR 的新方法。 MAP3K4 抑制组蛋白脱乙酰酶 6 (HDAC6) 的表达和活性。 KI 滋养层 HDAC6 表达升高和活性，HDAC6 的减少可恢复 IGF1R 和 IR 的表达和活性。基于这些发现，我们假设 HDAC6 在 KI 胎盘中也可能过度活跃，抑制 HDAC6 可能会挽救和防止 FGR。高选择性和耐受性良好的 HDAC6 抑制剂的出现提供了独特的开发治疗 FGR 的疗法的机会。然而，目前尚不清楚是否以 HDAC6 为目标怀孕会改善胎儿和胎盘的生长。我们的初步数据表明，HDAC6 的抑制怀孕提高了 KI 胚胎在发育过程中的存活率。然而，这次救援可能部分归因于 HDAC6 抑制剂的脱靶效应。检验我们的预测，即删除 HDAC6 将阻止 KI 中的 FGR 小鼠，我们建议通过将 MAP3K4 KI 小鼠与 HDAC6 敲除小鼠交配，从基因上删除 HDAC6 老鼠。将评估缺乏 HDAC6 的 MAP3K4 KI 小鼠的存活和生长。此外，胎儿和胎盘将测量胎盘的大小，并对 IGF1R、IR 和 Akt 的胎盘表达和活性进行量化。这些新结果将与 HDAC6 升高时观察到的生长限制和致死率进行比较。我们预测从 MAP3K4 KI 个体中删除 HDAC6 将改善胎儿生长并提高存活率，表明HDAC6抑制剂可能代表治疗FGR的新治疗工具。