F32 Fellowship for Study of Hedgehog Signaling in Postnatal Lung

F32 产后肺部刺猬信号研究奖学金

• 批准号: 8724982
• 负责人: Matthias Christian Kugler
• 金额: $ 4.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2015-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724982
• 关键词: Adenoviruses; Adult; Affect; Alveolar; Alveolus; Animal Model; Apoptosis; Asthma; Basic Science; Biology; Birth; Bronchopulmonary Dysplasia; Cells; Cellular biology; Chronic Obstructive Airway Disease; Complement; Defect; Development; Developmental Biology; Developmental Cell Biology; Disease; Down-Regulation; Dysbarism; Embryo; Embryonic Development; Epithelial; Equilibrium; Erinaceidae; Ethics; Event; Extracellular Matrix; Fellowship; Fibrosis; Foundations; Gases; Genetic; Goals; Grant; Heart; Human; Infection; Injury; Lead; Left; Light; Link; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Mediating; Mentors; Mesenchymal; Mesenchymal Differentiation; Methodology; Morphogenesis; Mus; Pathway interactions; Phase; Phenotype; Play; Premature Infant; Process; Processed Genes; Proteins; Pulmonary Emphysema; Pulmonary Fibrosis; Reading; Receptor Cell; Relative (related person); Reporter; Research; Research Project Grants; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sonic hedgehog protein; Staging; Stress; Structure; Surface; System; Testing; Time; Training; Training Programs; Withdrawal; Work; Writing; base; bone; cigarette smoking; design; experience; gain of function; inhibitor/antagonist; interest; interstitial cell; loss of function; lung development; lung injury; morphogens; mouse model; oxygen toxicity; pollutant; postnatal; public health relevance; research study; response; skills; smoothened signaling pathway; spatial relationship; stem cell biology

DESCRIPTION (provided by applicant): This is an application for F32 fellowship support for two years. During the fellowship period, the applicant will work on elucidating the role of Hedgehog (Hh) signaling in postnatal lung development. Hh signaling is mediated by three similar proteins (Sonic, Indian and Desert Hh) acting on the cell receptor Patched, and typically affects function of mesenchymal cells. Hedgehog signaling has been known for some time to be critical during embryonic development, but only recently has it come to be appreciated that Hh signaling affects disease processes such as cancer and fibrosis. Hedgehog signaling plays a major in branching morphogenesis in embryonic lung development but it is currently unknown what role this pathway plays during the final developmental steps of the lung. This final, postnatal phase of lung development involves creation of secondary septa, and maturation of these septal walls in a poorly understood process involving loss of interstitial cells. It is also postulated that developmental pathways such as Hh are reactivated in pulmonary fibrosis. The research plan is designed to test the hypothesis that proper timing of Hh signaling down-regulation is critical for the proper maturation of septal walls. The hypothesis states that Hh signaling in early postnatal lung development supports vigorous expansion of mesenchymal cells, whereas withdrawal of signaling at the end of the alveolarization phase contributes to a relative loss of mesenchymal cells due to some combination of reduced proliferation and increased apoptosis. The Aims to test this consist of, first, detailed analysis of the precise timig of Hh signaling during this period, measured using reporter mice that read-out Hh signaling, measurement by qRT-PCR of downstream transcriptional targets of Hh signaling such as Gli1, and direct measurement of Shh protein levels. In addition, in the second Aim, the effects of augmenting or inhibiting Hh signaling during the two phases will be determined and compared with predictions based on the hypothesis. To pursue this work and training, the applicant will work in the basic science lab of Dr. Dan Rifkin, acting chair of Cell Biology at NYU, who has a strong mentoring record and a wide range of research interests (cancer, fibrosis, and development of lung, heart and bone) that have extracellular matrix biology as a common thread. He will also pursue graduate level course work in Cell Biology, developmental systems, and stem cell biology, along with focused work related to grant writing, presentation skills and the ethical conduct of research. This research experience and related training are designed to augment his prior extensive research experience in pulmonary fibrosis and leave him poised to investigate questions of lung development, lung fibrosis and injury, and the involvement of developmental signaling pathways in adult lung processes and disease.

描述（由申请人提供）：这是一份为期两年的F32奖学金支持申请。在奖学金期间，申请人将致力于阐明Hedgehog（Hh）信号在出生后肺发育中的作用。Hh信号传导由作用于细胞受体Patched的三种类似蛋白质（Sonic、Indian和Desert Hh）介导，并且通常影响间充质细胞的功能。一段时间以来，Hedgehog信号在胚胎发育过程中至关重要，但直到最近才意识到Hh信号影响疾病过程，如癌症和纤维化。Hedgehog信号在胚胎肺发育的分支形态发生中起主要作用，但目前尚不清楚该途径在肺的最终发育步骤中起什么作用。出生后肺发育的最后阶段包括继发性隔膜的形成，以及这些隔膜壁的成熟，这一过程涉及间质细胞的损失，人们对此知之甚少。还假设发育途径如Hh在肺纤维化中被重新激活。 该研究计划旨在验证Hh信号下调的适当时机对于室间隔壁的适当成熟至关重要的假设。该假说指出，Hh信号在出生后早期肺发育支持间充质细胞的蓬勃发展，而在肺泡化阶段结束时的信号撤回有助于间充质细胞的相对损失，由于增殖减少和凋亡增加的一些组合。测试这一点的目的包括，首先，详细分析在此期间Hh信号传导的精确最小值，使用读出Hh信号传导的报告小鼠测量，通过qRT-PCR测量Hh信号传导的下游转录靶标如Gli 1，并直接测量Shh蛋白水平。此外，在第二个目标中，将确定在两个阶段期间增强或抑制Hh信号传导的效果，并与基于假设的预测进行比较。 为了从事这项工作和培训，申请人将在纽约大学细胞生物学代理主席Dan Rifkin博士的基础科学实验室工作，他拥有强大的指导记录和广泛的研究兴趣（癌症，纤维化和肺，心脏和骨骼的发展），这些都是细胞外基质生物学作为共同的线索。他还将继续研究生水平的课程工作，在细胞生物学，发育系统，干细胞生物学，沿着重点工作有关赠款写作，演讲技巧和研究的道德行为。这项研究经验和相关培训旨在增强他先前在肺纤维化方面的广泛研究经验，并使他能够研究肺发育，肺纤维化和损伤以及成人肺过程和疾病中发育信号通路的参与等问题。