Manipulating hTERT splicing in lung cancer cells.

操纵肺癌细胞中的 hTERT 剪接。

基本信息

  • 批准号:
    9764287
  • 负责人:
  • 金额:
    $ 24.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The vast majority (>85%) of human cancers use telomerase as the primary telomere length maintenance mechanism. My long-term goal is to establish an independent research laboratory, where I will elucidate the molecular mechanisms by which alternative splicing plays a role in telomere length maintenance mechanisms. This basic biological information will be important for my long-term goals for designing telomerase specific cancer therapeutics. The K99/R00 career award will help me in achieving my goals as a research scientist by advancing my training in: gene expression regulation, alternative splicing, next generation sequencing, and molecular biology under the co-mentorship of Dr. Woodring Wright, as well as cancer cell biology and models of cancer cell phenotypes under the co-mentorship of Dr. Jerry Shay. This training and guidance will compliment my previous training in gene expression, muscle biology, and cell signaling. The scientific environment at UT Southwestern Medical Center is extremely stimulating and will provide me with the facilities necessary for the completion of the mentored phase of this project and will prepare me to transition smoothly into the independent faculty phase. hTERT expression is developmentally regulated and has several splice variants. Only full-length hTERT mRNA produces catalytically active telomerase. Upon differentiation into mature tissue telomerase activity is down-regulated and only non-catalytically active hTERT splice variants remain. However, upon transformation to cancer, the majority of cancer types express full-length hTERT and have functional telomerase activity that helps to maintain the already very short telomeres in precancerous lesions. The transcriptional activation of hTERT has been widely studied, but the regulation of hTERT alternative splicing is almost entirely unknown. In Aim 1, during the K99 phase, I will define the role of NOVA1 that I identified in two different RNAi screens, in the regulation of hTERT splicing, telomere length, and telomerase activity. I will determine if NOVA1 binds hTERT pre-mRNA directly (CLIP) or in a protein complex (RIP). I will also define the role of NOVA1 in cancer cell alternative splicing by RNA sequencing. In Aim 2, during the K99 phase, I will use two xenograft models of tumor progression to determine if reduced levels of NOVA1 result in less metastases and tumor progression via inhibition of telomerase. During the R00 phase, Aim 3, I will characterize the regulation of NOVA1's 3'UTR in cancer cells and the potential of using a NOVA1 3'UTR reporter for small molecule screening to find a novel telomerase inhibitor. I will also continue to decipher the "hTERT splicing code" I discovered during my mentored phase with the goal of finding novel means to inhibit telomerase in cancer. These studies should lead to a robust research program into how alternative spicing participates and regulates telomere length maintenance mechanisms in cancer cells.


项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Acute Exercise Regulates hTERT Gene Expression and Alternative Splicing in the hTERT-BAC Transgenic Mouse Model.
  • DOI:
    10.1249/mss.0000000000002868
  • 发表时间:
    2022-06-01
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Slusher, Aaron L.;Kim, Jeongjin J. J.;Ribick, Mark;Ludlow, Andrew T.
  • 通讯作者:
    Ludlow, Andrew T.
Droplet Digital TRAP (ddTRAP): Adaptation of the Telomere Repeat Amplification Protocol to Droplet Digital Polymerase Chain Reaction.
Droplet Digital TRAP (ddTRAP):将端粒重复扩增方案应用于 Droplet Digital 聚合酶链式反应。
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Andrew Todd Ludlow其他文献

Andrew Todd Ludlow的其他文献

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{{ truncateString('Andrew Todd Ludlow', 18)}}的其他基金

Manipulating hTERT splicing in lung cancer cells.
操纵肺癌细胞中的 hTERT 剪接。
  • 批准号:
    9267141
  • 财政年份:
    2016
  • 资助金额:
    $ 24.3万
  • 项目类别:

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