Research Initiation Award: Non-apoptotic Functions for Fas-associated Death Domain (FADD) in Osteosarocma

研究启动奖为历史悠久的黑人学院和大学的初级和职业生涯中期教师提供支持，这些教师正在建立新的研究计划或重新定向和重建现有的研究计划。预计该奖项将(1)促进教师的研究能力和有效性，(2)改善本国机构的研究和教学，(3)吸引更多来自代表性不足群体的本科生参与研究体验。该项目来自德克萨斯南方大学，历史上是一所黑人学院/大学(HBCU)，旨在研究带有死亡结构域(FADD)的Fas相关蛋白在骨肉瘤(OS)生物学中的非凋亡功能。具体目标包括研究(1)死亡配体诱导细胞死亡的作用机制；(2)FADD在细胞内稳态活动中的作用。该项目包括指导两名德克萨斯南方大学本科生的研究经验。带有死亡结构域的Fas相关蛋白最初被发现是一种促进Fas介导的细胞凋亡的适配蛋白。随后的研究报告了FADD在免疫细胞中的非凋亡功能。FADD在肿瘤中的非凋亡功能还没有被广泛研究，在骨肉瘤(OS)中也没有关于FADD的非凋亡功能的报道。骨肉瘤是儿童和青少年中最常见的骨癌类型。Printon Investigator先前曾报道，FADD表达减少会使OS对死亡配体诱导的细胞死亡敏感，这表明FADD保护OS免受死亡配体诱导的细胞死亡。本研究的目的是研究FADD的非凋亡功能，以及与FADD的非凋亡功能相关的信号通路在肿瘤，特别是OS中的作用。本研究的具体目的是：1)确定死亡配体诱导的FADD状态改变的OS细胞死亡的作用机制；2)阐明FADD在细胞稳态中的作用，包括对氧化应激、细胞增殖和细胞周期的调节。FADD的表达水平、FADD的细胞定位和FADD的磷酸化影响FADD的功能。为了研究FADD的非凋亡功能，将使用三种OS细胞模型：1)FADD表达降低的细胞，2)FADD核定位受损的细胞，3)FADD磷酸化受抑的细胞。提出的实验方法研究了FADD的不同细胞状态对FADD功能的影响。评估支持生存和支持死亡的信号通路以及支持生存和支持死亡的分子的表达将有助于阐明死亡配体诱导FADD状态改变的OS细胞死亡的机制。将评估三种OS细胞模型中的细胞生长、细胞活力、代谢活性和细胞周期调节，以确定FADD状态改变对细胞稳态的影响。这项调查的结果将有助于更好地了解FADD在OS中的功能，并将作为FADD在其他癌症中的生物学功能研究方向的基础。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Research Initiation Awards provide support for junior and mid-career faculty at Historically Black Colleges and Universities who are building new research programs or redirecting and rebuilding existing research programs. It is expected that the award will (1) further the faculty member's research capability and effectiveness, (2) improve research and teaching at the home institution, and (3) engage more undergraduate students from underrepresented groups in research experiences. The project from Texas Southern University, a Historically Black College/University (HBCU), seeks to study the non-apoptotic functions of the Fas-associated protein with death domain (FADD) protein in osteosarcoma (OS) biology. The specific objectives include the investigation of (1) the mechanism of action responsible for death ligand-induced cell death; and (2) the role of FADD in cellular homeostatic activities. The project includes mentoring two Texas Southern University undergraduate students in research experience. Fas-associated protein with death domain was initially discovered as an adaptor protein that facilitates Fas-mediated apoptosis. Subsequent studies reported non-apoptotic functions of FADD in immune cells. Non-apoptotic functions of FADD have not been extensively studied in cancer, and no reports are available on non-apoptotic functions of FADD in osteosarcoma (OS). Osteosarcoma is the most common type of bone cancer found in children and teens. The Principle Investigator has previously reported that decreased FADD expression sensitizes OS to death ligand-induced cell death, indicating that FADD protects OS against death ligand-induced cell death. The aim of this study is to investigate the non-apoptotic functions of FADD as well as the signaling pathways associated with the non-apoptotic functions of FADD in cancer, specifically OS. The specific objectives of this research are: 1) to determine the mechanism of action responsible for death ligand-induced cell death in OS with altered FADD status and 2) to elucidate the function of FADD in cell homeostasis to include regulation of oxidative stress, cell proliferation and regulation of cell cycle. Level of FADD expression, cellular localization of FADD and FADD phosphorylation affects FADD function. To investigate the non-apoptotic functions of FADD, three OS cell models will be used: 1) cells with reduced expression of FADD, 2) cells with impaired nuclear localization of FADD, and 3) cells with inhibited FADD phosphorylation. The experimental approach presented investigates the different cellular states of FADD that affect FADD function. Assessment of pro-survival and pro-death signaling pathways and expression of pro-survival and pro-death molecules will elucidate mechanisms responsible for death ligand-induced cell death in OS with altered FADD status. Cell growth, cell viability, metabolic activity, and cell cycle regulation in the three OS cell models will be assessed to determine the impact of altered FADD status on cell homeostasis. The results generated from this investigation will contribute to a better understanding of FADD function in OS and will serve as a basis for the direction of research on the biological function of FADD in other cancers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.