The role of Nkx2-1 in the distal lung

Nkx2-1 在远端肺中的作用

• 批准号: 9758704
• 负责人: Nicholas Hedemann Juul
• 金额: $ 7.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758704
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Adult; Affect; Air; Air Sacs; Alleles; Alveolar; Alveolus; Amaze; Antibodies; Appearance; Belief; Biological Assay; Biology; Birth; Blood; Brain; Bronchopulmonary Dysplasia; Cancer Etiology; Carbon Dioxide; Cell Line; Cell Lineage; Cells; Chronic Obstructive Airway Disease; Development; Disease; Distal; Electron Microscopy; Embryo; Epithelial; Epithelial Cells; Expression Profiling; Functional disorder; Genes; Genetic; Homeobox; Human; Image; Immunofluorescence Immunologic; In Situ; In Situ Hybridization; Infant; Ligation; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Maps; Medicine; Mentors; Morphogenesis; Morphology; Mus; Mutation; Oxygen; Physicians; Point Mutation; Primitive foregut structure; Proteins; RNA; Role; Science; Scientist; Series; Stem cells; Syndrome; TAC1 gene; Techniques; Technology; Testing; Thyroid Gland; Tight Junctions; Work; adenoma; alveolar epithelium; cancer cell; cell type; combat; experimental study; idiopathic pulmonary fibrosis; in vivo; induced pluripotent stem cell; infancy; new technology; novel; occludin; respiratory distress syndrome; respiratory health; reverse genetics; single-cell RNA sequencing; stem cell biology; stem cell therapy; tool; transcription factor; tumor

THE ROLE OF NKX2-1 IN THE DISTAL LUNG The air sacs in the lung where oxygen and carbon dioxide are exchanged between the blood and the air are lined by alveolar epithelial cells. These cells are essential for respiratory health, and their dysfunction is associated with a range of serious diseases from birth (neonatal chronic lung disease and bronchopulmonary dysplasia) to adulthood (chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer). The key regulator of lung epithelial identity is NK2 homeobox 1 (NKX2-1), a transcription factor without which lungs do not even form in mammals. There are two types of alveolar epithelial cells, type 1 cells (AT1) and type 2 cells (AT2). Conventional wisdom maintains that NKX2-1 is only present in AT2 cells. However, the evidence for this belief is somewhat mixed, and we have strong evidence that NKX2-1 is also present and functional in AT1 cells. This project will use a novel technology developed in our lab to directly and definitively image the presence of Nkx2-1 in the adult mouse lung with a focus on AT1 cells. In order to then understand the actual function of Nkx2-1 in AT1 cells, we will use genetically altered mice to delete the Nkx2-1 gene in AT1 cells in the adult mouse lung and conduct detailed studies to understand how the loss of Nkx2-1 changes the AT1 cells. It is thought that the most common form of lung cancer, adenocarcinoma, comes from AT2 cells in part because lung adenocarcinoma has Nkx2-1 in it, and, as mentioned, Nkx2-1 is thought to be an AT2 marker. To determine if these Nkx2-1 tumors could actually be coming from AT1 cells, we will insert a cancer causing mutation into AT1 cells. We hypothesize that the resulting tumors will also be Nkx2-1 positive and similar in appearance to a specific type of human lung cancer called adenocarcinoma in situ. Knowing what kind of cell a cancer comes from is incredibly important in knowing how it turns into a cancer. If our hypothesis is indeed correct, this will change our understanding of where at least a portion of human lung cancers come from, thereby affecting our strategy of how to combat those cancers. This project will use the most powerful tools available in biology, including a new technology invented in our lab, to understand the role of Nkx2-1 in alveolar epithelial cells. As we transition into an era of generating specific types of cells for stem cell treatments, knowing how Nkx2-1, a “master regulator” of lung differentiation, works will be essential in developing stem cell treatments for lung disease.

NKX2-1在远端肺中的作用 肺中的气囊，氧气和二氧化碳在这里交换 血液和空气中排列着肺泡上皮细胞。这些细胞对于呼吸来说是必不可少的 健康，他们的功能障碍从出生起就与一系列严重疾病有关(新生儿 慢性肺病和支气管肺发育不良)至成年期(慢性阻塞性 肺部疾病、特发性肺纤维化和肺癌)。肺的关键调节因子 上皮细胞的特征是NK2同源框1(NKX2-1)，一种转录因子，没有NKX2-1，肺不能 甚至在哺乳动物身上也是如此。 肺泡上皮细胞有两种类型，1型细胞(AT1)和2型细胞(AT2)。 传统观点认为，NKX2-1只存在于AT2细胞中。然而，有证据表明 因为这种看法有些复杂，我们有强有力的证据表明，NKX2-1也存在， 在AT1细胞中起作用。这个项目将使用我们实验室开发的一项新技术来直接 并确定Nkx2-1在成年小鼠肺中的存在，重点放在AT1细胞上。 为了了解Nkx2-1在AT1细胞中的实际功能，我们将在遗传学上使用 改变小鼠以删除成年小鼠肺AT1细胞中的Nkx2-1基因，并进行详细的 研究Nkx2-1的缺失如何改变AT1细胞。 人们认为最常见的肺癌形式--腺癌--来自于 AT2细胞的部分原因是肺腺癌中有Nkx2-1，如前所述，Nkx2-1是 被认为是AT2的标志。为了确定这些Nkx2-1肿瘤是否真的来自 在AT1细胞中，我们将在AT1细胞中插入一种导致突变的癌症。我们假设 由此产生的肿瘤也将是Nkx2-1阳性，在外观上类似于特定类型的人类 肺癌称为原位腺癌。知道癌症来自哪种细胞就是 在了解它是如何演变成癌症方面非常重要。如果我们的假设确实是正确的，这 将改变我们对至少一部分人类肺癌来自哪里的理解， 从而影响我们如何抗击这些癌症的战略。 这个项目将使用生物学中最强大的工具，包括一个新的 本实验室发明的技术，以了解Nkx2-1在肺泡上皮细胞中的作用。因为我们 过渡到为干细胞治疗产生特定类型细胞的时代，知道如何 Nkx2-1是肺分化的“主要调节器”，它的工作对干细胞的发展至关重要。 肺部疾病的治疗。