WNT5a Regulates Lung Maturation

摘要 胎儿器官的成熟以支持出生后的生命是一个重要的重要过程。然而，在大多数情况下， 这一过程没有得到很好的调查/理解。在肺中，成熟失败是一种重要的健康 有问题。在早产儿中，它会导致呼吸窘迫综合征(RDS)和支气管肺 发育不良(BPD)。 我们已经发现，非典型WNT配体WNT5A的功能丧失会抑制肺成熟。 两个关键缺陷包括肺泡1型上皮细胞(AEC1)分化抑制和肺泡型 肌成纤维细胞(AMF)分化。重要的是，反之亦然；WNT5a函数增益 促进肺成熟和AEC1分化。在其他的初步研究中，我们表明- Wnt5A受体ROR1和ROR2的功能导致与Wnt5A类似的肺成熟缺陷 功能丧失。WNT5A激活钙/钙调素依赖的蛋白激酶II(CaMKII) 胞质信号转导分子。抑制CaMKII也会扰乱肺的成熟。基于 综合初步发现，我们提出了以下假设： 假设：Wnt5A-ROR信号是肺成熟的关键调节因子。这条途径控制着 结构、细胞和分子步骤，最终有助于形成有功能的肺。 在这个应用中，我们将重点研究AEC1和AMF分化，作为两个关键的细胞机制 肺成熟过程中受Wnt5A调控。多个组织特异性的、有条件的体内模型 肺成熟期间AEC和AMF中的靶Wnt5a和RORS将被用来确定其细胞类型 球囊和肺泡期的特殊功能。这些研究还将确定CaMKII的作用为 WNT5A调解员。我们提出了以下具体目标。 具体目的1.探讨Wnt5A信号在AEC肺成熟过程中的作用。 具体目的2.探讨Wnt5A信号在AMF肺发育成熟过程中的作用。 具体目的3.确定CaMKII作为下游细胞内介质的作用 Wnt5A信号在肺成熟中的作用 健康相关性：肺成熟是出生后生存的一个生存要求。如果成功， 这项研究的结果可能会对理解这种机制产生有意义的影响 潜在的肺成熟，这可能有助于开发更有效和新的肺部治疗方法 早产儿的疾病。确定Wnt5A、RORS和CaMKII在肺成熟中的作用 进一步建议不同水平的信号转导的治疗靶点&可能允许更多的选择性 这一过程的调制。

ABSTRACT Maturation of fetal organs to support life after birth is a significantly vital process. However, in most cases, this process is poorly investigated/understood. In the lung, failure in maturation is a significant health problem. In preterm infants, it can cause Respiratory Distress Syndrome (RDS) and BronchoPulmonary Dysplasia (BPD). We have found that loss-of-function for a non-canonical WNT ligand, WNT5a inhibits lung maturation. Two key defects include inhibition of alveolar type 1 epithelial cell (AEC1) differentiation and alveolar myofibroblast (AMF) differentiation. Importantly, the converse is also true; Wnt5a gain-of-function promotes lung maturation & AEC1 differentiation. In additional preliminary studies, we show that loss-of- function of WNT5a receptors, ROR1 and ROR2, results in similar defects in lung maturation as in WNT5a loss-of-function. WNT5a activates Calcium/calmodulin-dependent protein kinase II (CaMKII) an important cytoplasmic signal transduction molecule. Inhibiting CaMKII also disrupts lung maturation. Based on the collective preliminary findings, we propose the following hypothesis: HYPOTHESIS: WNT5a-ROR signaling is a key regulator of lung maturation. This pathway controls the structural, cellular and molecular steps that ultimately contribute to the formation of functional lungs. In this application, we will focus on AEC1 and AMF differentiation, as two key cellular mechanisms controlled by WNT5a during lung maturation. Multiple tissue specific, conditional in vivo models that target Wnt5a and Rors in AEC and AMF during lung maturation will be used to determine their cell-type specific functions in saccular and alveolar stages. The studies will also determine the role of CaMKII as WNT5a mediator. We propose the following Specific Aims. Specific Aim 1. To Determine the Function of WNT5a Signaling in AEC During Lung Maturation. Specific Aim 2. To Determine the Function of WNT5a Signaling in AMF During Lung Maturation. Specific Aim 3. To Determine the Role of CaMKII as a Downstream Intracellular Mediator of WNT5a Signaling in Lung Maturation. Health Relevance: Lung maturation is an existential requirement for surviving after birth. If successful, the results of this research will likely have a meaningful impact on understanding the mechanisms underlying lung maturation, which may help in development of more effective & novel therapies for lung diseases in premature infants. Determining the role of WNT5a, RORs & CaMKII in lung maturation could further suggest therapeutic targets at different levels of signal transduction & may allow for more selective modulation of this process.