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Diversity Supplement Carolina Galeano-Naranjo

多样性补充卡罗莱纳·加莱亚诺-纳兰霍

基本信息

批准号：
10811185
负责人：
Tianyan Gao
金额：
$ 6.72万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811185
关键词：
Automobile Driving Autophagocytosis Basic Cancer Research Cancer Etiology Cancer Patient Cell Death Induction Cell Migration Inhibition function Cell Proliferation Cell Survival Cells Cellular Stress Cessation of life Chemoresistance Collaborations Colon Carcinoma Colorectal Cancer Development Disease Down-Regulation EIF-2alpha Effectiveness Ensure Epithelial Cells Equilibrium Event Funding Grant HK2 gene Inflammation Integrins Intestines Knockout Mice Knowledge Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolism Mitochondria Molecular Mutation Oncogenic Organism PH Domain Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Physiological Play Protein Dephosphorylation Protein Family Protein Kinase Protein phosphatase Proto-Oncogene Proteins c-akt Regulation Resistance Role Signal Pathway Signal Transduction Stress Supporting Cell Testing Training Tumor Suppressor Proteins United States biological adaptation to stress cancer cell cancer initiation cancer survival cancer type cell growth regulation chemotherapy coping mechanism endoplasmic reticulum stress improved in vivo insight leucine-rich repeat protein mitochondrial autophagy mortality mouse model multicatalytic endopeptidase complex novel protein expression response sensor success translational cancer research tumor initiation tumor metabolism tumor progression tumorigenesis

项目摘要

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 145,000 new cases and 51,000 deaths are predicted for the year 2019; and this mortality is predominantly due to poor responses to available treatment options. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients. My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase), in inhibiting colon cancer initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to further develop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supporting cell survival and tumorigenesis. In exciting recent findings, we demonstrated that chemotherapy-induced ER stress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulating eIF2α/ATF4-mediated signaling. In addition, we found that downregulation of PHLPP promotes mitochondrial fission by regulating Drp1 phosphorylation. Collectively, the central hypothesis driving this proposed study is that PHLPP serves an essential stress sensor in CRC, in which cellular stress signals trigger PHLPP degradation to promote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecular mechanism underlying PHLPP-mediated regulation of eIF2α/ATF4 signaling. We will determine if downregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagy activation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics; and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumor initiation and progression in colon cancer. This supplement will allow Ms. Carolina Galeano-Naranjo to receive further training in conducting basic and translational cancer research. Her results will assist in determining the role of PHLPP in CRC by regulating mitochondrial activity. She will determine if PHLPP mutations found in CRC patients interfer with their ability to control Drp1 phosphorylation and mitochondrial fission. Ultimately, by providing mechanistic insights into PHLPP-dependent regulation of stress response, our findings will help identify new treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status in cancer patients.

结直肠癌是美国癌症相关死亡的第二大原因。大约 2019年预计新增病例145,000例，死亡人数51,000例；这种死亡率主要是由于对现有治疗方案反应不佳。更好地理解导致的分子事件为了提高癌症患者的总体生存率，需要癌症进展和化疗耐药性。我的实验室一直致力于阐明新型蛋白磷酸酶家族 PHLPP 的作用（PH 结构域富含亮氨酸重复蛋白磷酸酶），抑制结肠癌的发生和进展。我们在理解 PHLPP 作为肿瘤抑制因子的功能重要性方面取得了实质性进展以及PHLPP调控的分子机制。本研究的总体目标是进一步发展对 PHLPP 介导的细胞应激反应调节的机制理解，以支持细胞存活和肿瘤发生。在令人兴奋的最新发现中，我们证明化疗诱导的 ER 压力促进 PHLPP 降解，PHLPP 损失通过上调提供生存优势 eIF2α/ATF4 介导的信号传导。此外，我们发现 PHLPP 的下调会促进线粒体通过调节 Drp1 磷酸化来进行裂变。总的来说，推动这项拟议研究的中心假设是 PHLPP 在 CRC 中充当重要的压力传感器，其中细胞压力信号触发 PHLPP 降解促进细胞存活和肿瘤发生。提出以下具体目标：1）描绘分子 PHLPP 介导的 eIF2α/ATF4 信号传导调节的机制。我们将确定是否 PHLPP 的下调使结肠癌细胞因自噬而对化疗药物产生耐药性激活; 2) 确定PHLPP介导的线粒体动力学调节的功能重要性； 3) 确定线粒体动力学在与 PHLPP 损失配合促进肿瘤发生中的作用体内。我们的研究将填补关于线粒体动力学改变如何导致肿瘤的重要知识空白结肠癌的发生和进展。该补充品将使 Carolina Galeano-Naranjo 女士能够获得进行基础和转化癌症研究的进一步培训。她的结果将有助于确定 PHLPP 通过调节线粒体活性在 CRC 中发挥作用。她将确定结直肠癌中是否发现 PHLPP 突变患者控制 Drp1 磷酸化和线粒体裂变的能力受到干扰。最终，通过我们的研究结果提供了对 PHLPP 依赖性应激反应调节的机制见解，将有助于确定新的治疗方案，并根据 PHLPP 状态更好地预测化疗药物的有效性癌症患者。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.

DOI：
10.1038/onc.2008.450
发表时间：
2009-02-19
期刊：
ONCOGENE
影响因子：
8
作者：
Liu, J.;Weiss, H. L.;Rychahou, P.;Jackson, L. N.;Evers, B. M.;Gao, T.
通讯作者：
Gao, T.

Inverse agonism at the Na/K-ATPase receptor reverses EMT in prostate cancer cells.

DOI：
10.1002/pros.24144
发表时间：
2021-07
期刊：
The Prostate
影响因子：
0
作者：
通讯作者：

Beta-catenin cleavage enhances transcriptional activation.

DOI：
10.1038/s41598-017-18421-8
发表时间：
2018-01-12
期刊：
Scientific reports
影响因子：
4.6
作者：
Goretsky T;Bradford EM;Ye Q;Lamping OF;Vanagunas T;Moyer MP;Keller PC;Sinh P;Llovet JM;Gao T;She QB;Li L;Barrett TA
通讯作者：
Barrett TA

The leucine-rich repeat signaling scaffolds Shoc2 and Erbin: cellular mechanism and role in disease.

DOI：
10.1111/febs.15450
发表时间：
2021-03
期刊：
The FEBS journal
影响因子：
0
作者：
Jang H;Stevens P;Gao T;Galperin E
通讯作者：
Galperin E

mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.

DOI：
10.1158/0008-5472.can-10-4058
发表时间：
2011-05-01
期刊：
Cancer research
影响因子：
11.2
作者：
Gulhati P;Bowen KA;Liu J;Stevens PD;Rychahou PG;Chen M;Lee EY;Weiss HL;O'Connor KL;Gao T;Evers BM
通讯作者：
Evers BM