Molecular and biochemical basis of Lymphangioleiomyomatosis

淋巴管平滑肌瘤病的分子和生化基础

基本信息

批准号：
9197682
负责人：
JOHN BLENIS
金额：
$ 50.27万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197682
关键词：
Abnormal Cell Address Adverse effects Affect Alternative Splicing Angiomyolipoma Animals Area Arginine Benign Biochemical Biochemistry Biogenesis Biological Markers Biological Process Biology Breast Epithelial Cells Cell Proliferation Cell Survival Cells Cellular biology Citric Acid Cycle Clinical Clinical Trials Complex Cytostatics Diabetes Mellitus Disease Disease Progression Drug Targeting Energy Supply Estrogen Receptors Estrogens Extracellular Signal Regulated Kinases FRAP1 gene Family Female Fibronectins Genes Genetic Glucose Glutamine Goals Growth Growth Factor Human Immune System Diseases In Vitro Individual Infiltration Lesion Life Link Lung Lymphangioleiomyomatosis Lymphatic Lymphatic vessel MAPK3 gene MEKs Malignant Neoplasms Mediating Messenger RNA Metabolic Metabolism Methods Molecular Mus Mutation Neoplasm Metastasis Normal Cell Null Lymphocytes Nutrient Oncogenic Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Phosphotransferases Play Pleural effusion disorder Pneumothorax Positioning Attribute Process Property Protein Kinase Protein Splicing Proteins Publishing RNA Splicing Rattus Receptor Signaling Regulation Research Respiratory Failure Role Serine Signal Pathway Signal Transduction Sirolimus Smooth Muscle Source Spliced Genes Stem cells System TSC1 gene TSC2 gene Testing Therapeutic Therapeutic Intervention Toxic effect Translating Translations Tuberous Sclerosis Tuberous sclerosis protein complex Tumor Suppressor Genes Uterine Fibroids Vascular Endothelial Growth Factors Withholding Treatment Woman Work airway obstruction analog base cell growth cell motility child bearing drug development drug discovery epithelial to mesenchymal transition expectation improved in vivo in vivo Model inhibitor/antagonist insight loss of function macromolecule migration novel novel strategies novel therapeutics nutrient deprivation personalized therapeutic phosphoproteomics protein expression public health relevance pulmonary function response small hairpin RNA targeted treatment transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Pulmonary Lymphangioleiomyomatosis (LAM) is a slowly progressing disease characterized by cystic destruction of the lungs and eventual respiratory failure, and affects 3.4-7.8 per million women. Biochemically, LAM is caused by loss of function of the Tuberous Sclerosis Complex (TSC) and appears to require activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Despite encouraging clinical trial results from the use of mTORC1 inhibitors to treat LAM, these drugs are limited for two reasons: first, rapamycin-based treatments are not curative as tumors regrow following cessation of treatment; and second, long-term rapamycin usage has tremendous side effects including immune disorders and diabetes. To resolve this currently, unmet clinical need, this project will investigate three unresolved mechanistic questions, with the long-term goal of developing long-lasting therapies for LAM. The first aim will determine the contribution of glutamine (Gln) metabolism in AML and LAM cells and its importance in cellular survival as inability of mTORC1-targeted therapies to induce toxicity remains an unaddressed hurdle. This aim will investigate the mechanism of Gln metabolism in these cells as well as new approaches to target the growth and survival of AML and LAM cells via pharmacologic and shRNA methods, both in vitro and in vivo. The second aim will garner a greater understanding of how the mTORC1 pathway regulates the alternative splicing of key genes involved in the "benign metastasis" phenotype seen in LAM. While mRNA splicing is highly regulated and pervasive (occurring in ~95% of human genes and frequently deregulated in cancer), the mechanisms causing deregulation are unknown. Using novel hits from a phospho-proteomic screen we recently completed, this aim will investigate how the mTORC1 pathway regulates the splicing of key genes involved in the "benign metastasis" phenotype of LAM. Finally, the third aim will identify key mechanistic insights into how estrogen contributes to the pathogenesis of LAM, which occurs almost exclusively in females during childbearing years. The aim will investigate the role of estrogen receptor signaling via the ERK-Fra1-ZEB pathway, in the context of mTORC1 hyperactivation, in regulating LAM cell survival, migration and invasion. In addition to addressing basic questions of LAM biology, each of these aims has clinical implications, and in two of the aims animal studies have been proposed to translate the cell biology discoveries into relevant in vivo models. In conclusion, there's a great need for greater understanding of the biology of LAM, and the expectations are that successful completion of the proposed work will impact LAM treatment through identification of new biomarkers as well as novel drugs that can specifically eliminate abnormal cell growth, migration and tumor formation in TSC and LAM patients.

描述（由申请人提供）：肺淋巴管平滑肌瘤病 (LAM) 是一种进展缓慢的疾病，其特征是肺部囊性破坏和最终呼吸衰竭，每百万女性中有 3.4-7.8 人患有这种疾病。从生化角度来看，LAM 是由结节性硬化症复合物 (TSC) 功能丧失引起的，并且似乎需要激活哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 信号通路。尽管使用 mTORC1 抑制剂治疗 LAM 的临床试验结果令人鼓舞，但这些药物因两个原因而受到限制：首先，基于雷帕霉素的治疗没有疗效，因为停止治疗后肿瘤会重新生长；其次，长期使用雷帕霉素会产生巨大的副作用，包括免疫紊乱和糖尿病。为了解决目前未满足的临床需求，该项目将研究三个未解决的机制问题，长期目标是开发 LAM 的长效疗法。第一个目标是确定谷氨酰胺 (Gln) 代谢在 AML 和 LAM 细胞中的作用及其在细胞存活中的重要性，因为 mTORC1 靶向疗法无法诱导毒性仍然是一个尚未解决的障碍。该目标将研究这些细胞中 Gln 代谢的机制，以及通过体外和体内药理学和 shRNA 方法靶向 AML 和 LAM 细胞生长和存活的新方法。第二个目标是更好地了解 mTORC1 通路如何调节参与 LAM 中“良性转移”表型的关键基因的选择性剪接。虽然 mRNA 剪接受到高度调控且普遍存在（存在于约 95% 的人类基因中，并且在癌症中经常失调），但导致失调的机制尚不清楚。利用我们最近完成的磷酸化蛋白质组筛选的新结果，该目标将研究 mTORC1 通路如何调节参与 LAM“良性转移”表型的关键基因的剪接。最后，第三个目标将确定雌激素如何促进 LAM 发病机制的关键机制，这种疾病几乎只发生在育龄期的女性中。目的是研究在 mTORC1 过度激活的情况下，雌激素受体信号通过 ERK-Fra1-ZEB 通路在调节 LAM 细胞存活、迁移和侵袭中的作用。除了解决 LAM 生物学的基本问题外，这些目标中的每一个都具有临床意义，并且在其中两个目标中，已提出动物研究以将细胞生物学发现转化为相关的体内模型。总之，非常需要对 LAM 的生物学有更深入的了解，并且期望成功完成拟议的工作将通过识别新的生物标志物以及能够特异性消除异常细胞生长、迁移的新药物来影响 LAM 治疗TSC 和 LAM 患者的肿瘤形成。