Erik S. Knudsen - US grants

tumor suppressor proteins; retinoblastoma protein; cell growth regulation; cell cycle; cell proliferation; cyclins; phosphorylation; immunoglobulin G; genetic promoter element; oncogenes; genetic regulation; neoplastic process; cell line; transfection; microinjections; neoplastic cell; tissue /cell culture;

retinoblastoma protein; gene environment interaction; cyclins; retinoblastoma; oncoproteins; gene expression; genetic polymorphism; phosphorylation; protein structure function; environment related neoplasm /cancer; cyclin dependent kinase; cell growth regulation; tumor suppressor genes; gene induction /repression; gene mutation; cancer risk; DNA damage; cell proliferation; disease /disorder model; neoplastic process; southern blotting; western blottings; laboratory mouse; genetically modified animals; polymerase chain reaction; flow cytometry;

[unreadable] DESCRIPTION (provided by applicant): To improve cancer therapy, it is increasingly critical that advances in basic cancer research be translated to the clinic. In the Training Program in Cancer Therapeutics, the goal is to provide training to cancer researchers in the action of therapeutic agents used in the treatment of cancer. This Training Program will be multi-disciplinary and expose the trainees to both basic research involving cancer therapeutic agents and the clinical utilization of therapeutics. A particular emphasis will be placed on the mechanisms through which basic scientific discovery is brought into the clinic through clinical trials. To facilitate this training, a team of mentoring faculty and ancillary clinical faculty has been recruited into the Training Program from the University of Cincinnati and Cincinnati Children's Hospital Medical Center. All mentors on this training program are independently funded, have experience in mentoring, and work on projects related to cancer therapy. The ancillary faculty are clinical partners on this proposal, who will educate on the clinical utilization of specific therapeutic modalities. Together, the mentors and ancillary faculty will provide training both through direct interactions and through specialized educational activities and course work for the Training Program. This Program will provide outstanding career development for trainees, as more emphasis is placed on translating basic scientific discovery into improved patient care. [unreadable] [unreadable] Logistically, the Training Program in Cancer Therapeutics has 19 mentors and 6 ancillary faculty. It is administered by the Principal Investigator and Administrative Committees, which are directed at training excellence and providing an ethnically and scientifically diverse group of trainees. The Training Program requests support for 6 postdoctoral and 2 predoctoral trainees. The program will be evaluated regularly through both internal and external review to ensure that the trainees are receiving the best possible training. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Liver cancer is the third leading cause of cancer deaths throughout the world. The major risk factors for development of this disease are environmental in nature. These risk factors include agents that strongly modulate tumor susceptibility such as chronic infection with hepatitis B virus or exposure to the DNA damaging hepatocarcinogen aflatoxin B1 (AFB1). Tumor development is largely driven by genetic lesions that subvert critical cellular pathways. 1 such pathway, the retinoblastoma tumor suppressor (RB) pathway is mutated in the majority of liver tumors. Although RB is mutated in most liver tumors, how RB loss specifically contributes to tumorigenesis in the liver is unknown. Furthermore, the interplay between RB-deficiency and exposure to the environmental agents that cause liver cancer, e.g. AFB1, and how this impacts tumor formation is unclear. This is a critical consideration because it is well established that RB is required for the appropriate cell cycle checkpoint response to DNA damage. In the absence of RB, cells continue to proliferate in the presence of DNA damage, inducing additional mutations and leading to genome instability, a hallmark of cancer cells. Critically, the role of RB in DNA damage checkpoints in animals and how checkpoint abrogation contributes to tumorigenesis has not been studied. We have generated mice that have hepatocyte-specific RB-deficiency. We have found that RB deficiency causes abnormal hepatocyte ploidy (total DNA content), suggesting that these cells are inherently genetically unstable. We have also found that RB loss predisposes to the induction of liver tumors following genotoxic damage. Thus, we hypothesize that RB loss enhances tumor formation in the liver following exposure to environmentally-relevant genotoxic carcinogens, such as AFB1. We propose to delineate how RB modifies the response to AFB1 in the mouse liver and probe how this contributes to tumor formation. First, we will determine how RB loss influences the acute checkpoint response of the liver to AFB1 exposure and identify features of this aberrant response (e.g. development of genome instability) that may be important for driving tumor formation. Second, we will specifically elucidate the effects of RB-loss on AFB1-induced liver tumor development in the mouse. These studies will identify critical facets of RB function in vivo and delineate specific consequences of RB loss that are germane to tumor formation following genotoxic insult. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Liver cancer is the third leading cause of cancer deaths throughout the world. The major risk factors for development of this disease are environmental in nature. These risk factors include agents that strongly modulate tumor susceptibility such as chronic infection with hepatitis B virus or exposure to the DNA damaging hepatocarcinogen aflatoxin B1 (AFB1). Tumor development is largely driven by genetic lesions that subvert critical cellular pathways. 1 such pathway, the retinoblastoma tumor suppressor (RB) pathway is mutated in the majority of liver tumors. Although RB is mutated in most liver tumors, how RB loss specifically contributes to tumorigenesis in the liver is unknown. Furthermore, the interplay between RB-deficiency and exposure to the environmental agents that cause liver cancer, e.g. AFB1, and how this impacts tumor formation is unclear. This is a critical consideration because it is well established that RB is required for the appropriate cell cycle checkpoint response to DNA damage. In the absence of RB, cells continue to proliferate in the presence of DNA damage, inducing additional mutations and leading to genome instability, a hallmark of cancer cells. Critically, the role of RB in DNA damage checkpoints in animals and how checkpoint abrogation contributes to tumorigenesis has not been studied. We have generated mice that have hepatocyte-specific RB-deficiency. We have found that RB deficiency causes abnormal hepatocyte ploidy (total DNA content), suggesting that these cells are inherently genetically unstable. We have also found that RB loss predisposes to the induction of liver tumors following genotoxic damage. Thus, we hypothesize that RB loss enhances tumor formation in the liver following exposure to environmentally-relevant genotoxic carcinogens, such as AFB1. We propose to delineate how RB modifies the response to AFB1 in the mouse liver and probe how this contributes to tumor formation. First, we will determine how RB loss influences the acute checkpoint response of the liver to AFB1 exposure and identify features of this aberrant response (e.g. development of genome instability) that may be important for driving tumor formation. Second, we will specifically elucidate the effects of RB-loss on AFB1-induced liver tumor development in the mouse. These studies will identify critical facets of RB function in vivo and delineate specific consequences of RB loss that are germane to tumor formation following genotoxic insult. [unreadable] [unreadable] [unreadable]