NF-Kappa B regulation by Bcl10 in liver cancer

简介（由申请人提供）：Lakita G， Cavin博士，自2001年6月以来一直是田纳西大学Marcello Arsura博士实验室的博士后研究实习生，在那里她在一个有关核因子- kappab （NF-kappaB）在肝癌发生中的作用的项目中发挥了突出作用。在培训期间获得的经验和知识激励她在学术界寻求一个独立的职位，在那里她将领导一个有能力的科学家和研究人员团队，进一步追求她对肝癌研究的兴趣。过去，由于乙型和丙型肝炎病毒感染的增加，美国肝细胞癌（hcc）的发病率及其发病率一直在稳步上升。因此，需要更好地了解导致肝肿瘤进展的机制，以设计更有效的治疗hcc的方法。Gavin博士的研究表明，通过保护细胞死亡和诱导细胞生长，构成核因子- kappab （NF-kappaB）激活在肝脏肿瘤进展中起作用。虽然NF-kappaB在肝脏肿瘤发生过程中的作用已被证实，但NF-kappaB激活的机制仍有待确定。在初步研究中，候选人已经表明表皮生长因子受体（EGFR）信号和BcMO基因在实验来源的小鼠hcc中NF-kappaB激活中发挥作用。因此，她的提案计划确定BcMO-和egfr介导的NF-kappaB激活在肝脏肿瘤进展中的生化参数和功能后果。在特定的Aim 1中，Cavin博士将确定bcl10介导的ikk - γ泛素化在tgf - α /c-myc双基因hcc中NF-kappaB异常激活过程中的作用。在Aim 2中，她将确定EGFR/P(l)3K/Akt轴对NF-KappaB组成性激活和小鼠和人hcc细胞存活的功能影响。最后，在Aim 3中，她将确定NF-kappaB激活中EGFR/PI(3)K/Akt轴与BcMO/IKK-gamma通路之间的相互作用。在肝脏肿瘤发展过程中导致NF-kappaB激活的途径的表征将为开发NF-kappaB小分子抑制剂作为肝癌治疗的潜在佐剂提供场所。

DESCRIPTION (provided by applicant): Dr. Lakita G, Cavin, the Candidate, has been a postdoctoral research trainee at the University of Tennessee in the lab of Dr. Marcello Arsura since June 2001 where she has played a prominent role in a project pertaining to the role of nuclear factor-kappaB (NF-kappaB) during hepatic oncogenesis. The experience and the knowledge gained during her training has inspired her to seek an independent position in academia where she will lead a team of capable scientist and researchers to further pursue her interests in liver cancer research. Over the past, the incidence rate of hepatocellular carcinomas (HCCs) as well as its morbidity in the U. S. has been steadily increasing due to an increment of hepatitis B and C viral infections. Thus, a better understanding of the mechanism/s leading to hepatic tumor progression is needed to design more effective therapies for the treatment of HCCs. Dr. Gavin's studies have implicated constitutive nuclear factor-kappaB (NF-kappaB) activation in liver neoplastic progression through protection from cell death and induction of cell growth. While the function of NF-kappaB during hepatic oncogenesis is well established, the mechanism/s of NF-kappaB activation still remains to be identified. In preliminary studies, the Candidate has shown that epidermal growth factor receptor (EGFR) signaling and the BcMO gene play a role in NF-kappaB activation in experimentally derived murine HCCs. Thus, her proposal plans to determine the biochemical parameters and functional consequences of BcMO- and EGFR-mediated activation of NF-kappaB in liver tumor progression. In specific Aim 1, Dr. Cavin will determine the role of Bcl10-mediated ubiquitination of IKK-gamma during aberrant activation of NF-kappaB in TGF-alpha/c-myc bitransgenic HCCs. In Aim 2, she will determine the functional impact of the EGFR/P(l)3K/Akt axis in constitutive activation of NF-KappaB and cell survival of murine and human HCCs. Finally, in Aim 3, she will determine the interplay between the EGFR/PI(3)K/Akt axis and the BcMO/IKK-gamma pathway in NF-kappaB activation. The characterization of the pathway/s leading to NF-kappaB activation during liver neoplastic development will provide venues for the development of small molecule inhibitors of NF-kappaB as potential adjuvants for liver cancer treatment.