Mechanism and Regulation of Baxdelta2 in Colorectal Cancer

Baxdelta2在结直肠癌中的作用机制及调控

基本信息

批准号：
9021169
负责人：
JIALING XIANG
金额：
$ 45.85万
依托单位：
ILLINOIS INSTITUTE OF TECHNOLOGY
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：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021169
关键词：
Alternative Splicing Apoptotic Applications Grants Awareness Biomedical Research CASP5 gene CASP8 gene Cell Death Cells Cessation of life Characteristics Clinical Code Colon Carcinoma Colorectal Cancer Colorectal Neoplasms DNA Damage Development Discipline Environment Exons Frameshift Mutation Genes Genomics Hereditary Nonpolyposis Colorectal Neoplasms Illinois Image Induced Mutation Institutes Lead Malignant Neoplasms Mediating Microsatellite Instability Microsatellite Repeats Mismatch Repair Mitochondria Molecular Mutate Mutation PTEN gene Pathway interactions Patients Phenotype Protein Isoforms Proteins Regulation Research Resources Students Subgroup System Technology Therapeutic Thinking Transcript Tumor Suppressor Proteins Universities Work animal facility biological research biomedical facility cancer cell colon cancer patients design education research experience graduate student innovation loss of function neoplastic cell outcome forecast premature prototype public health relevance research study sensor tumor tumor growth tumorigenesis undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Expression of the pro-apoptotic tumor suppressor Bax can be silenced by frameshift mutations in its microsatellite coding region, leading to a Bax-negative phenotype. Such Bax mutations occur in ~50% of hereditary nonpolyposis colorectal cancer (HNPCC) due to deficiency of mismatch repair system associated microsatellite instability (MSI). Loss of Bax has been demonstrated to increase chemoresistance and is associated with poor prognosis. Recently, we found that some "Bax-negative" tumor cells actually contain a functional Bax isoform, BaxΔ2, which is generated when alternative splicing corrects the mutation-induced frameshift. Therefore, BaxΔ2 only exists in microsatellite-mutated cells. We have demonstrated that this "salvaged" Bax∆2 is pro-death, similar to prototype Bax, but induce cell death potential through a non- mitochondrial death pathway. Importantly, colon cancer cells expressing Bax∆2 are more sensitive to selected chemotherapeutics. Therefore, we hypothesize that BaxΔ2 determines tumor malignant potential and chemotherapeutic selectivity in "Bax-negative" MSI colorectal cancer cells through a non-canonical Bax- death pathway. We have two specific aims: 1) to study the mechanism underlying Bax∆2-mediated cell death; and 2) to identify key regulators responsible for controlling Bax∆2 expression levels in MSI colorectal tumor cells. Since there was no awareness of the existence of a Bax isoform in the "Bax-negative" cancer prior to this study, we think the studies proposed in this grant application are conceptually innovative and significant because they will change the current paradigm for understanding the development and prognosis of the "Bax-negative" MSI colorectal cancer and facilitating selection of specific chemotherapeutics for this subgroup of "Bax-negative" colon cancer patients. The Illinois Institute of Technology (IIT) is a private university with a wide range of academic disciplines. The University encourages biological research and promotes integrative biomedical research with potential translational impact. IIT currently lacks several biomedical facilities, such as high-level genomic and imaging facilities, a full-featured animal facility, and clinical resources. However, IIT does have a large body of undergraduate and graduate students eager to participate in biomedical research. The PI has a strong academic credential for both education and research. The proposed project is carefully designed to exploit the strengths of IIT's research environment and maximize opportunities for student hands-on research experiences. Successful completion of the proposed studies will have a substantial positive impact on IIT's biomedical research capacity.

描述（由适用提供）：促凋亡肿瘤抑制bax的表达可以被其微卫星编码区域中的移码突变沉默，从而导致Bax阴性表型。由于缺乏不匹配修复系统相关的微卫星不稳定性（MSI），这种BAX突变发生在约50％的遗传非型结直肠癌（HNPCC）中。 BAX的丧失已被证明可以增加化学抗性，并且预后不良。最近，我们发现某些“ Bax阴性”肿瘤细胞实际上包含功能性BAX同工型BaxΔ2，当替代剪接纠正突变诱导的移屏时会生成。因此，BaxΔ2仅存在于微卫星突破的细胞中。我们已经证明，这种“挽救”的baxΔ2是亲死亡的，类似于原型Bax，但通过非线粒体死亡途径衍生出细胞死亡势。重要的是，表达BaxΔ2的结肠癌细胞对选定的化学疗法更敏感。因此，我们假设BaxΔ2通过非典型的BAX-死亡途径确定了“ Bax阴性” MSI结直肠癌细胞中肿瘤恶性潜力和化学治疗选择性。我们有两个具体的目的：1）研究BaxΔ2介导的细胞死亡的机制； 2）确定负责控制BaxΔ2表达水平的关键调节器在MSI结直肠肿瘤细胞中。由于在本研究之前的“ Bax阴性”癌症中没有对BAX亚型存在的意识，因此我们认为，本赠款应用中提出的研究在概念上具有创新性和重要意义，因为它们将改变当前的范式，以了解“ Bax-negative” MSI结论性化学癌症患者的“ Bax-negative” MSI癌症和对Sumotherapity colorecticist的选择。伊利诺伊理工学院（IIT）是一所私立大学，拥有广泛的学科。该大学鼓励生物学研究并促进综合的生物医学研究，并具有潜在的转化影响。 IIT目前缺乏几个生物医学设施，例如高级基因组和成像设施，功能齐全的动物设施和临床资源。但是，IIT确实有大量的本科生和研究生渴望参加生物医学研究。 PI对教育和研究具有强大的学术证书。拟议的项目经过精心设计，旨在探索IIT研究环境的优势以及学生动手研究经验的最大机会。成功完成拟议的研究将对IIT的生物医学研究能力产生重大积极影响。