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Mechanisms of autophagy in TSC1-deficient neural stem cells

TSC1缺陷神经干细胞的自噬机制

基本信息

批准号：
9165268
负责人：
Chenran Wang
金额：
$ 7.9万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9165268
关键词：
Adopted Affect Area Astrocytoma Autoimmune Diseases Autophagocytosis Benign Body part Brain Brain Neoplasms Breast Cancer Cell Cell physiology Cells Chloroquine Complex Data Defect Development Disease Disease model Energy-Generating Resources Event Exhibits FRAP1 gene Family Frequencies Genes Genetic Glycolysis Glycolysis Inhibition Goals Growth Hematopoietic stem cells Hereditary Disease Homeostasis In Vitro Investigation Knock-out Knockout Mice Knowledge Lead Lesion Life Link Maintenance Malignant Neoplasms Mammary gland Mediating Metabolic Methods Modeling Molecular Mus Mutation Neurodegenerative Disorders Neurons Nodule Organ Organelles PTK2 gene Pathogenesis Patients Prevention Proteins Public Health Regulation Research Role Signal Pathway Signal Transduction Somatic Cell Starvation Stem Cell Development Stem cells Stream Stress Subependymal Subependymal Giant Cell Astrocytoma System TSC1 gene Testing Therapeutic Effect Tuberous sclerosis protein complex Tumor Suppressor Proteins base clinically relevant developmental disease genetic approach in vivo innovation lateral ventricle mTOR inhibition malformation migration mouse model neoplastic cell nerve stem cell novel novel therapeutics prevent response self-renewal targeted treatment tool treatment stratification tumor tumor initiation tumorigenesis

项目摘要

PROJECT SUMMARY Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in brain and many other parts of the body. This disease affects as many as 50,000 people in US. TSC often affects brain and the tumors of subependymal giant astrocytoma (SEGA) can cause serious or life-threatening complications. The mutations of Tsc1 or Tsc2 gene leading to the loss of their tumor suppressor functions to control the activity of mTOR underlie the pathogenesis of TSC. mTOR stimulates the activity of S6K and 4EBP1 and is a negative regulator of autophagy. However, recent findings, including ours, revealed a higher autophagy level in TSC1-deficient neurons and TSC1-deficient mammary gland tumor cells under energy stress with high mTOR activity, suggesting unrecognized functions of autophagy in TSC1-deficient cells. To further understand the complex interplay between autophagy and mTOR signaling, we established a novel double conditional knockout (cKO) mouse model to delete TSC1 and FIP200, an essential component in autophagy induction complex, in neural stem cells (NSCs). This model also provides a unique tool to study the mechanism of autophagy in abnormal development and tumorigenesis of SEN/SEGA from TSC-deficient NSCs. Our preliminary findings indicated that FIP200 mediated autophagy was indispensable to maintain the high activity of mTOR and was crucial for the tumorigenesis of SEN/SEGA in TSC1-deficient NSCs. In addition, we found that autophagy was used to sustain high mTOR activity in TSC1-deficient cells under the context of glycolysis inhibition, which is a well-known but not totally clarified phenomenon. These findings form the basis of our hypothesis that autophagy satisfies the high energy demanding in TSC1-deficient NSCs with limited energy source supply to maintain their high mTOR activity and tumorigenesis. In Aim1 of this proposal, we will exam the molecular events to induce autophagy, as well as the mechanism of autophagy to regulate signaling pathways and metabolic activity to maintain high mTOR activity using the in vitro cultured NSCs from TSC1 cKO and TSC1/FIP200 double cKO mice. In Aim2, we will adopt pharmacological methods to inhibit autophagy and glycolysis in TSC1-deficient NSCs to test the feasibility of tumor prevention of SEN/SEGA in TSC1 cKO mice. At the end of these studies, we will expand our knowledge of TSC pathogenesis, identify candidate key signaling pathways and metabolic alterations, and develop new therapeutic concepts for continued investigation into the treatment of an important disorder.

项目总结