Mitochondrial quality control as a selective vulnerability in cancers with chromosome 10q deletion

线粒体质量控制作为染色体 10q 缺失癌症的选择性脆弱性

• 批准号: 10597590
• 负责人: Jacob Michael Winter
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597590
• 关键词: 10q; ATP phosphohydrolase; Affect; Animal Model; Apoptosis; Apoptotic; BCL2 gene; BCL2L11 gene; BH3 peptide; Back; Biochemistry; CRISPR screen; CRISPR/Cas technology; Cancer Patient; Cause of Death; Cell Culture System; Cell Death; Cell Fractionation; Cell Line; Cell Proliferation; Cell Respiration; Cell Survival; Cells; Cellular biology; Chromosome 10; Chromosomes; Clinical; Communities; DNA; Dedications; Dermatology; Development; Diagnosis; Drug Targeting; Family member; Fluorescence Microscopy; Gene Deletion; Genes; Genetic; Genomics; Glioblastoma; Homeostasis; Human; Impairment; In Vitro; Individual; Induction of Apoptosis; Length; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Mammalian Cell; Measures; Metastatic Prostate Cancer; Mitochondria; Mitochondrial Proteins; Mus; Mutation; Normal Cell; Null Lymphocytes; Outer Mitochondrial Membrane; PTEN gene; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Physicians; Predisposition; Process; Prognosis; Proteins; Quality Control; Regulation; Research; Research Personnel; Research Training; Resolution; Role; Scientist; Signal Pathway; Synthetic Genes; System; Tail; Talents; Testing; Therapeutic; Training; Transmembrane Domain; Tumor Suppressor Genes; United States; Universities; Utah; Xenograft procedure; cancer cell; cancer therapy; career; cell growth; clinical development; clinical training; del(10q23); experience; fitness; genome-wide; in vivo; medical specialties; melanoma; mimetics; mouse model; new therapeutic target; novel; novel therapeutic intervention; precision oncology; prevent; professor; skills; small molecule; trait; tumor; tumor progression

PROJECT ABSTRACT In the development and progression of cancer, cells frequently delete large regions of DNA that include tumor suppressor genes (TSGs). By virtue of proximity, genes that neighbor TSGs are often co-deleted, which usually does not affect cell fitness. Nonetheless, deletion of a gene as a passenger mutation can make a cancer cell vulnerable to drugs or other mutations in ways that healthy, genetically “normal” cells are not. Targeting such vulnerabilities to kill cancer cells and leave healthy cells unharmed evokes the genetic principle of “synthetic lethality.” Two mutations are said to be synthetic lethal when cells tolerate either one individually, but die when they occur together. Thus, identification of genes that are synthetic lethal with co-deleted genes can provide new drug targets. One of the most frequently deleted tumor suppressor genes in cancer is PTEN, which encodes a phosphatase that normally antagonizes cell growth and survival. Only 40 kilobases upstream of the human PTEN locus on chromosome 10q23 is the locus for ATAD1, which encodes an evolutionarily conserved ATPase that is essential for mitochondrial homeostasis. ATAD1 extracts tail-anchored (TA) proteins from the outer mitochondrial membrane (OMM). TA proteins possess a single-pass transmembrane domain at the C- terminus. We conducted a genome-wide CRISPR screen to identify genes that are essential only in the absence of ATAD1, as these would make ideal drug targets for tumors that co-delete ATAD1 with PTEN. Multiple hits from our screen implicate ATAD1 in the regulation of apoptosis, a process that critically depends on TA proteins in the OMM. Specifically, translocation to the OMM by a class of TA proteins known as BH3- only proteins is thought to induce apoptosis. We hypothesize that ATAD1 extracts tail-anchored BH3-only proteins from the outer mitochondrial membrane to prevent aberrant apoptosis. The present proposal describes how we will test this hypothesis using genetics, biochemistry, and animal models. Small molecule mimetics of BH3-only proteins are approved for use in cancer patients, and thus the connection between ATAD1 and apoptosis could have major implications for precision oncology. Together with my sponsors I have generated a research training plan that integrates clinical training and will prepare me for a career as a physician-scientist. My research training plan will help me develop skills in cell biology and biochemistry, which are the specialties of my primary sponsor, Dr. Jared Rutter, and his lab. My clinical training sponsor, Dr. Douglas Grossman, is a physician-scientist and Professor of Dermatology, and he will help me gain clinical experience that emphasizes the diagnosis and treatment of cancer. I will conduct research in the vibrant community of the Department of Biochemistry at the University of Utah, which houses a diverse group of talented investigators dedicated to training young scientists.

项目摘要 在癌症的发展和进展中，细胞经常删除包括肿瘤细胞在内的大部分DNA区域。 抑制基因（TSGs）。由于邻近性，邻近TSG的基因通常是共缺失的， 通常不会影响细胞的健康。尽管如此，作为乘客突变的基因的缺失可以使一个人的基因发生突变。 癌细胞易受药物或其他突变的影响，而健康的、遗传上“正常”的细胞则不然。 针对这些弱点杀死癌细胞并使健康细胞不受伤害，这唤起了遗传学原理 “合成杀伤力”当细胞单独耐受其中一个突变时， 但当它们同时出现时就会死亡因此，鉴定具有共缺失基因的合成致死基因， 可以提供新的药物靶点。 在癌症中最常缺失的肿瘤抑制基因之一是PTEN，其编码一种与肿瘤相关的蛋白。 通常拮抗细胞生长和存活的磷酸酶。人类的上游只有40个酶 染色体10 q23上的PTEN基因座是ATAD 1的基因座，其编码进化上保守的 ATP酶是线粒体稳态所必需的。ATAD 1从细胞中提取尾锚定（TA）蛋白。 线粒体外膜（OMM）。TA蛋白在C-端具有一个单通道跨膜结构域， 终点站我们进行了全基因组CRISPR筛选，以确定仅在人类免疫系统中必需的基因。 ATAD 1缺失，因为这些将成为ATAD 1与PTEN共缺失的肿瘤的理想药物靶标。 我们筛选的多个结果表明ATAD 1参与了细胞凋亡的调节，这一过程严重依赖于 在OMM中的TA蛋白。具体地，通过一类称为BH 3的TA蛋白易位至OMM。 只有蛋白质被认为诱导细胞凋亡。我们假设ATAD 1只提取尾部锚定的BH 3- 蛋白质从线粒体外膜，以防止异常凋亡。现时的建议 描述了我们将如何使用遗传学，生物化学和动物模型来测试这一假设。小分子 BH 3-only蛋白的模拟物被批准用于癌症患者，因此BH 3-only蛋白的模拟物与癌症患者之间的联系被证实是可能的。 ATAD 1和细胞凋亡可能对精确肿瘤学有重要意义。 我和我的赞助商一起制定了一个研究培训计划， 为我将来成为一名科学家做好准备我的研究培训计划将帮助我发展技能 细胞生物学和生物化学，这是我的主要赞助人贾里德·鲁特博士和他的实验室的专业。 我的临床培训赞助商，道格拉斯格罗斯曼博士，是一位医学科学家和皮肤病学教授， 他将帮助我获得临床经验，重点是癌症的诊断和治疗。我会指挥 在犹他州大学生物化学系充满活力的社区进行研究，该社区设有一个 一群有才华的研究人员致力于培养年轻科学家。