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Modulating Stochastic Gene Expression for Cell-fate Control and Therapeutics

调节随机基因表达以控制细胞命运和治疗

基本信息

批准号：
10362710
负责人：
Leor S Weinberger
金额：
$ 91.84万
依托单位：
J. DAVID GLADSTONE INSTITUTES
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：
2014-06-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362710
关键词：
Address Affect Architecture Attenuated Award Bacteria Cell Fate Control Cells Cellular biology Chemosensitization Circadian Rhythms Clinical Data Development Electrophysiology (science)Embryo Embryonic Development Engineering Enhancers Evolution FDA approved Feedback Flow Cytometry Gene Expression Genes Genetic Genetic Transcription Goals HIV Heterogeneity Intervention Knowledge Lead Literature Malignant Neoplasms Mammalian Cell Maps Modeling Molecular Neurosciences Noise Nuclear Export Outcome Pathway interactions Pharmacology Regulator Genes Reporter Research Rest Role Safety Science Sensorimotor functions Source Starvation Stress System T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Effect Transcription Coactivator Translations Viral Virus Diseases Virus Latency Work Yeasts base biological systems cell fate specification circadian clinical translation drug repurposing effective therapy embryonic stem cell improved in vivo knock-down mathematical model molecular modeling mutant novel novel therapeutic intervention predictive modeling reactivation from latency stem cells therapeutic development therapeutic target tool transcriptome

项目摘要

PROJECT SUMMARY Stochastic fluctuations in gene expression are unavoidable at the single-cell level and affect fate decisions from HIV to embryonic development. Yet, there remain fundamental gaps in our understanding of the mechanisms generating and regulating expression fluctuations in mammalian cells. Addressing this gap in knowledge is critical to therapeutic development in systems where fluctuations and heterogeneity present treatment barriers, such as in HIV, stem-cell therapeutics, and cancer. Our long-term goal is to develop therapeutics that target mechanisms of cellular heterogeneity to overcome barriers to precise control of cell fate. During the past 5 years, our work established mechanistic roles for noise and heterogeneity, demonstrating that noise is a feature, rather than a bug, of biological systems that can be modulated for therapeutic effect. Specifically, we: (i) elucidated a viral transcriptional-feedback circuit that harnesses noise to regulate HIV latency, (ii) found this circuit to be optimized by evolution to function as a viral bet-hedging circuit, (iii) made contributions to cell biology showing that transcriptional fluctuations are, in general, amplified by nuclear export and translation, and, (iv) we discovered a novel post-transcriptional feedback architecture that efficiently suppresses noise to stabilize fate commitment. Most excitingly, and most relevant to this application, we (v) discovered noise- enhancer molecules that appear to substantially improve viral reactivation from latency and have been used by other labs to increase noise in diverse systems (e.g., circadian rhythm). The objective of this renewal is to identify molecular mechanisms of noise modulation in mammalian cell-fate circuits to enable therapeutic control of noise. Based on our findings and extensive preliminary evidence in embryonic stem cells (ESCs), our central hypothesis is that generalized `core' cellular mechanisms exist to tune expression noise and that these mechanisms can be pharmacologically perturbed. Our specific aims build off our unique tool of noise-enhancer molecules and will: (Aim 1) map the molecular mechanistic pathways of noise enhancer molecules to develop a mathematical model predictive of transcriptome-wide noise in mammalian cells; (Aim 2) map the molecular mechanisms of noise-suppressor molecules; and (Aim 3) to quantify relative contributions of stochastic vs. deterministic mechanisms underlying HIV latency in vivo and safety & efficacy of noise-modulating molecules in vivo. The proposed research has broad significance as it will determine core molecular mechanisms regulating expression in disparate fate-specification models, reveal genetic targets of noise enhancement and suppression that can lead to the development of new broad-spectrum noise modulators, and propel clinical translation of noise-modulating molecules. Ultimately, the knowledge gained will guide new therapeutic approaches to overcome barriers to precise cell-fate control across diverse mammalian systems.

项目总结