NF-Kappa B regulation by Bcl10 in liver cancer

描述（由申请人提供）：候选人Lakita G，Cavin博士自2001年6月以来一直是田纳西大学Marcello Arsenal博士实验室的博士后研究实习生，在那里她在一个关于核因子-kappaB（NF-kappaB）在肝肿瘤发生过程中的作用的项目中发挥了重要作用。在培训期间获得的经验和知识激励她在学术界寻求独立的职位，在那里她将领导一支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，肝细胞癌（HCC）的发病率及其在美国的发病率一直处于上升趋势。S.由于B型和C型肝炎病毒感染的增加，因此，需要更好地理解导致肝肿瘤进展的机制，以设计更有效的治疗HCC的疗法。Gavin博士的研究表明，组成性核因子-κ B（NF-κ B）通过保护细胞免于死亡和诱导细胞生长而在肝脏肿瘤进展中活化。虽然NF-κ B在肝肿瘤发生过程中的功能已得到充分证实，但NF-κ B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）信号传导和BcMO基因在实验衍生的小鼠HCC中的NF-κ B活化中发挥作用。因此，她的提案计划确定肝肿瘤进展中BcMO和EGFR介导的NF-κ B激活的生化参数和功能后果。在具体目标1中，Cavin博士将确定Bcl 10介导的IKK-γ泛素化在TGF-α/c-myc双转基因HCC中NF-κ B异常激活期间的作用。在目标2中，她将确定EGFR/P（I）3 K/Akt轴在NF-KappaB的组成性激活和鼠和人HCC的细胞存活中的功能影响。最后，在目标3中，她将确定EGFR/PI（3）K/Akt轴和BcMO/IKK-γ通路在NF-κ B活化中的相互作用。在肝肿瘤发展过程中导致NF-κ B活化的途径的表征将为开发NF-κ B的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.