Xinbin Chen - US grants

DESCRIPTION: (adapted from the investigator's abstract) Mutation of the p53 tumor suppressor gene is the most prevalent genetic change associated with human cancer. It is well established that accumulation of p53 following genotoxic stress results in cell cycle arrest and/or apoptosis. Both cell cycle arrest and apoptosis contribute to p53 tumor suppression. Genetic studies have shown a strong correlation between its ability to act as a transcriptional regulator and its cell cycle arrest function. However, it is less clear how p53 induces apoptosis. Recently the investigators have used a tetracycline-regulated promoter to generate a number of stable cell lines that inducibly express p53. The results show that p53 levels, functional domains and DNA damage determine the extent of the apoptotic response of tumor cells. In addition, they show that the p53 transcription-dependent and transcription-independent pathways of apoptosis are genetically separable and synergistically cooperate in inducting apoptosis. Further understanding of the mechanism of p53-dependent apoptosis will be vital to its application in cancer therapy. The specific aims are: (1) To delineate the functional domains of p53 that are required for apoptosis and its cooperation with various therapeutic drugs in inducing apoptosis. By generating and subsequently expressing various deletion and point mutants of p53 in the activation domain, the hinge region between the activation and sequence specific DNA binding domains, the nuclear localization signal, the oligomerization and carboxyl-terminal nonspecific DNA binding domains, the roles of these domains in p53-dependent apoptosis and cell cycle arrest will be analyzed in cells. By using cell lines inducibly expressing either wild-type or various mutated forms of p53, the domain(s) of p53 that cooperate with various therapeutic drugs in inducing apoptosis will be determined. (2) To identify and characterize potential mediators of p53-dependent apoptosis. By using differential display analysis, they have identified four novel potential p53 target genes. These genes will be characterized for their ability to confer p53-dependent apoptosis and cell cycle arrest. Additional p53 target genes will also be identified. Furthermore, by using cell lines that inducibly express the influenza hemagglutinin (HA)-tagged p53 protein, both immunoprecipitation and affinity chromatography will be performed to identify new potential p53-interacting proteins that may mediate p53 transcription-dependent apoptosis.

tumor suppressor proteins; protein structure function; p53 gene /protein; cell cycle proteins; genetic regulation; genetic mapping; cell cycle; gene expression; apoptosis; cell line; tissue /cell culture;

DESCRIPTION (provided by applicant): As a transcription factor, p53 exerts a tumor suppressor activity by regulating a diverse array of genes involved in the control of cell cycle, apoptosis, differentiation, and DNA repair. Since the last competitive review of this project, we have identified seven novel p53 target genes. For example, we have found that MCGIO can induce cell cycle arrest and apoptosis and TAP1 may mediate tumor surveillance. We have also found that p2lB, a variant of p2l WAF1, is expressed in the Golgi apparatus and can induce apoptosis. These results have led us to hypothesize that multiple, parallel cell cycle control and apoptotic pathways are involved in p53 tumor suppression. To explore these further, we propose: (1) To identify additional novel p53 target genes. We will use the Affymetrix GeneChip assay to identify additional p53 target genes involved in the control of the cell cycle and apoptosis. We will analyze patterns of gene expression in response to various levels of p53 activation. Furthermore, we will determine whether one or more p53 response elements are present in the promoter or introns of the induced genes, and whether p53 regulates, or binds to, the potential response element(s). (2) To determine the mechanism by which wild type p53 and various mutants differentially regulate gene expression. (3) To determine the role of p2lB and MCG1O in p53 tumor suppression. We will analyze the role of p21B in p53-dependent apoptosis by somatic gene targeting and the mechanism by which p21 B induces apoptosis from within the Golgi. We will also determine the role of MCG1O in p53 tumor suppression, the mechanism by which MCG1O regulates gene expression, and whether MCG10 mediates activation or repression of some p53 target genes.

DESCRIPTION (provided by applicant): The p63 protein, a member of the p53 family, is expressed in three major forms, p63a, p63b, and p63g. All three forms can be transcribed from a promoter located in intron 3, producing DNp63a, DNp63b, and DNp63g. p63 shares considerable sequence identity with p53, especially in the DNA binding, transactivation, and tetramerization domains. Like p53, p63 is a transcription factor capable of inducing cell cycle arrest, differentiation, and apoptosis. However, unlike p53 that plays an essential role in tumor suppression, p63 appears to be necessary for the maintenance and regeneration of epithelial stem cells. p63 deficiency in mice and heterozygous germline p63 mutations in humans lead to defects in limb, craniofacial, and epidermal morphogenesis. Recently, we showed that p63a and DNp63a differentially regulate p21, GADD45, and the p53 inducible gene 3 (PIG3). Furthermore, our preliminary data indicated that several genes, including plasminogen activator inhibitor 1 (PAl-l) and insulin-like growth Factor binding protein 3 (IGFBP3), are differentially regulated by various p63 isoforms. Since the transcriptional activity is necessary for p63 activity, we hypothesize that various p63 isoforms differentially regulate their target genes, which mediate the activity of p63 in inducing cell cycle arrest, differentiation, and apoptosis and are responsible for the distinct biological functions of p63. To further address these, we propose: (1) to identify and characterize novel target genes differentially regulated by various isoforms of p63; (2) to identify a p63-associated protein(s) that interacts with the sterile alpha motif (SAM) in p63 and is responsible for the differential gene regulation by the alpha and gamma variants of DNp63; and (3) to determine the mechanism by which some p63 isoforms differentially regulate the expression of p21, GADD45, IGFBP3, PIG3, and possibly, other novel p63 target genes.

DESCRIPTION (provided by applicant): p73, a member of the p53 tumor suppressor family, is involved in the DNA damage response and serves as a mediator of p53 tumor suppression. Like p53, p73 is a sequence-specific DNA-binding transcription factor and an important regulator in the control of the cell cycle and apoptosis, p73 is expressed as three major variants, TA, DN, and DTA. The TA variant is transcribed from the upstream promoter and produces at least seven alternatively spliced TA isoforms (p73a-h), which differ in their carboxyl termini. The DN variant is transcribed from an alternate promoter in intron 3 and similarly produces at least another seven alternatively spliced DN isoforms (DNp73a-h). Since the N-terminal activation domain is absent in the DN variant, it is hypothesized that the DN variant is transcriptionally inactive and potentially dominant negative over the TA variant and possibly over p53. Interestingly, we have found and, later several other groups have confirmed, that the DN variant of the p53 family member p63, which also lacks the N-terminal activation domain, is transcriptionally active and capable of inducing specific target genes. Thus, we hypothesize that DNp73 is transcriptionally active and exerts its function by regulating specific target genes. Since p73 is 63% identical in amino acid to p53 in the DNA-binding domain, it can regulate some p53 target genes, presumably via the p53 responsive element. However, we found that the functional domains in p73 are different from that in p53. We also found that while p73 regulates IGFBP3 and GADD45, it does not regulates a luciferase reporter under the control of the p53 responsive element found in both genes. Thus, we hypothesize that p73 regulates some target genes through its unique responsive element. These hypotheses will be addressed in three aims: (1) to analyze the activity of the DN variant of p73, (2) to determine the mechanism by which various p73 isoforms differentially regulate IGFBP3 and GADD45, and (3) to determine the role of IGFBP3 and GADD45 in mediating p73 function.

[unreadable] DESCRIPTION (provided by applicant): This application is proposed to address the molecular oncogenic properties of mutant p53. p53 tumor suppressor is a sequence-specific DNA-binding transcription factor. Wild-type p53 is activated in response to various stress signals, such as DNA damage, oncogene activation, and hypoxia. Following its activation, p53 suppresses damaged cells to proliferate by inducing downstream effects, such as cell cycle arrest and apoptosis. However, mutations in the p53 gene abrogate its transcriptional activity, leading to the uncontrolled proliferation characteristic of tumor cells. As a result, mutations of the p53 gene are selected for in greater than 50% of all human cancers. A vast majority of p53 mutations occur in its DNA-binding domain, rendering p53 defective in its DNA binding and transcriptional activities. This represents the classical loss of function mutation for a tumor suppressor. Interestingly, in addition to loss of function, many p53 mutants obtain additional activities, called gain of function. It is well known that in a cell carrying both wild-type and mutant p53, the mutant p53 acquires its gain of function by forming a heterotetramer with, and inhibiting the activity of, wild-type p53. However, the vast majority of tumor cells, which over-express a mutant p53, do not carry a wild-type p53. Thus, mutant p53 gain of function in these tumor cells must be due to its tumor-promoting activity independent of the inhibition of wild-type p53. To further analyze how mutant p53 obtains its gain of function, the following specific aims are proposed: (1) to determine whether mutant p53 is required for maintaining the transformed phenotypes of tumor cells in evading apoptosis and enhanced potentials in proliferation and invasion; (2) to determine whether various classes of p53 mutants differ in their ability to maintain the transformed phenotypes of tumor cells; and (3) to determine whether mutant p53 still functions as a transcription factor that regulates genes involved in promoting survival or inhibiting anti-growth signals. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): P63 is a member of the p53 family. When the upstream promoter is used for p63 expression, three major TAp63 isoforms, TAp63a, TAp63[unreadable], and TAp63?, are produced. p63 is also expressed from an alternate promoter located in intron 3, producing three major ?Np63 isoforms, ?Np63a, ?Np63[unreadable], and ?Np63?3. As a transcription factor, TAp63 and ?Np63 are capable of regulating both common and distinct groups of target genes. Due to its sequence similarity with p53 and its transcriptional activity, p63 has many p53-like functions, such as an ability to induce cell cycle arrest, apoptosis, differentiation, and senescence. Thus, p63 is a tumor suppressor. Consistent with this, p63 status has been linked to increased survival rates and loss of p63 expression has been linked to increased potentials in metastasis. Likewise, mice heterozygous for p63 developed an increased tumor burden and metastasis rate, which was compounded in mice harboring heterozygous alleles of p53 and/or p73. However, p63 is not a classic tumor suppressor since p63 is expressed primarily in epithelial cells and appears to be necessary for the differentiation, maintenance, and regeneration of epithelial stem cells. In addition, mutant mice have developmental abnormalities. In an effort to characterize p63 functional domains and transcriptional activity, we identified and characterized two p63 targets: RNPC1, a RNA-binding protein, and Dec1, a basic helix-loop-helix transcription factor. Interestingly, we also found evidence that both RNPC1 and Dec1 are capable of regulating p63 expression. Considering that some of the stress signals, such as DNA damage and hypoxia that stabilize and activate p53, are found to have an effect on p63 expression, it is still not clear how p63 expression is regulated. Thus, we hypothesize that RNPC1 and Dec1 are both an effector and a modulator of the p63 pathway. To test this, we will determine (1) whether various p63 isoforms are differentially regulated by RNPC1 and Dec1 and (2) the mechanism by which p63 expression is regulated by RNPC1 and Dec1. PUBLIC HEALTH RELEVANCE: P63 is a member of the p53 tumor suppressor family and known to play a role in tumor suppression. The proposed study is to determine how p63 expression is regulated by RNPC1 and Dec1, both of which are also regulated by p63. Listed below are some of the rationales why the proposed study is significant. First, given the fact that p63 is found to play a critical role in tumor suppression but very little is known about its expression, the proposed study will provide an insight into the mechanism by which various stress signals impact on p63 expression. Second, p63 is expressed as two major isoforms, TAp63 and ?Np63, which are differentially expressed in various cell types and tissues. In addition, these p63 isoforms have distinct transcriptional and biological activities. Thus, how these p63 isoforms are differentially regulated by RNPC1 and Dec1 may provide an insight into the mechanism by which the expression patterns and biological activities of p63 are regulated. Third, ?Np63 is found to be amplified and/or over-expressed in some tumors, such as head and neck squamous cell carcinoma, and correlated with tumor progression and poor prognosis. Thus, the regulation of ?Np63 expression by RNPC1 and Dec1 can be explored as a potential therapeutic strategy to manage tumors with amplified and/or over- expressed ?Np63.

DESCRIPTION (provided by applicant): The role of DNA polymerase eta in DNA damage response and p53 activation. This application is proposed to address the signaling pathway of DNA polymerase eta (PolH) in DNA damage response and p53 activation and the effect of the signal pathway interaction between p53 and PolH on cell survival and death. In an effort to characterize the role of p53 in DNA damage response, we found that PolH can be induced by DNA damage in a p53-dependent manner. PolH is the product of the Xeroderma Pigmentosum (XP) gene. XP is an autosomal recessive disorder, and XP patients are prone to early onset of malignant skin cancers. Interestingly, we found that knockdown of PolH enhances cell survival by inhibiting DNA damage-induced apoptosis. We also found that DNA damage-induced activation of p53 is impaired in both PolH-knockdown and PolH-null cells, which can be rescued by a reconstituted PolH. Furthermore, we found that PolH modulates DNA damage response via the ATM- ChK2-p53 pathway. Finally, our recent preliminary studies showed that the stability of PolH protein is decreased upon DNA damage and PolH physically interacts with Mdm2 and Pirh2, both of which are a p53 target gene and an E3 ligase. Taken together, we hypothesize that PolH activity is regulated by multiple pathways and PolH has novel functions in DNA damage response and p53 activation. To further address this, the following three specific aims are proposed: (1) to determine whether and how PolH expression is regulated at basal and DNA damage conditions;(2) to determine the functional significance of the interaction between PolH and Mdm2 or Pirh2;and (3) to determine the role of PolH in DNA damage response and p53 activation. PUBLIC HEALTH RELEVANCE: It is well-known that loss of p53 tumor suppressor leads to genome instability and Xeroderma Pigmentosum (XP) patients often exhibit a high frequency of genome instability. In addition, the magnitude of genome instability is much higher in cells lacking both Xeroderma Pigmentosum (XP) and p53 genes than cells lacking either one individually. Interestingly, we found that PolH, the XPV gene product, is a novel p53 target gene and knockdown of PolH enhances cell survival by inhibiting DNA damage-induced apoptosis. Surprisingly, we found that activation of p53 following DNA damage is impaired in both PolH-knockdown and PolH-null cells, which can be rescued by reconstituted PolH. Given the fact that loss of PolH predisposes XP patients to early onset of multiple malignant skin cancers and that p53 is a tumor suppressor, further studies to address how PolH modulates p53 activation and DNA damage response are highly significant and warranted.

DESCRIPTION (provided by applicant): Mutation of p53 is the most frequent genetic alteration in human cancer. The majority of tumor- derived p53 mutations is missense mutation and clustered within the central DNA-binding domain. Mutant p53 is defective in sequence-specific DNA binding and growth suppression, which defines the classical loss of function mutation. In addition, mutant p53 with an intact domain for tetramerization is dominant negative since the mutant can form a heterotetramer with wild-type p53. Moreover, mutant p53 acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knockn mice that carry one null allele and one mutant allele (R172H or R270H) of the p53 gene. These knockin mice develop aggressive tumors compared to p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for survival and resistance to DNA damage. Thus, the oncogenic properties of mutant p53 provide a rationale to target mutant p53 for cancer therapy, including the ones reactivating a mutant into wild-type-like. However, the large number of p53 mutations (> 2,314 types of mutations; ://www-p53.iarc.fr) poses a major challenge to develop versatile p53-reactivating drugs, especially considering that a modification and/or physical interaction is needed to convert a mutant into wild-type-like. Furthermore, a number of p53 mutants, when stabilized, associate with and inhibit other p53 family tumor suppressors (i.e., p63 and p73), which would then enhance gain of function for these p53 mutants. Thus, we hypothesize that targeting mutant p53 expression is a viable therapeutic strategy for tumors addicted to mutant p53. To further address this, three specific aims are proposed: (1) to determine how mutant p53 expression is transcriptionally regulated by histone deacetylases (HDACs), particularly HDAC8 and the biological significance of HDAC8 regulation of mutant p53 expression; (2) to determine the biological significance of RNPC1 regulation of mutant p53 expression and whether RNPC1 expression is suppressed in human tumors carrying a mutant p53; and (3) to determine how mutant p53 protein stability is regulated by arsenic and whether arsenic can suppress mutant p53-induced cell transformation and tumor progression.

DESCRIPTION (provided by applicant): Mechanism of p53-dependent tumor suppression Summary P53 tumor suppressor is activated in response to stress signals, including DNA damage and hypoxia. Upon activation, p53 induces a plethora of pro-survival and pro-apoptotic genes as well as the ones that in turn modulate p53 expression and activity. Among these is p21, a cyclin-dependent kinase inhibitor that mediates p53 to induce cell cycle arrest. Previously, we found that RNPC1, also called Rbm38 and a RNA- binding protein, is transcriptionally regulated by DNA damage in a p53-dependent manner. Interestingly, we found that RNPC1 directly binds to p21 transcript and enhances p21 mRNA stability. In addition, RNPC1 binds to p53 transcript and suppresses p53 mRNA translation. Thus, we identified p53-RNPC1 as a novel feedback loop in the p53 pathway. The significance of the loop is exemplified by our recent observations: (1) RNPC1 may play a central role in transmitting signals from Akt-GSK3 kinases and Wip1 -/- protein phosphatase to the p53 pathway and (2) RNPC1 MEFs are prone to premature senescence in a p53- -/- dependent manner and RNPC1 mice are prone to premature aging. These observations prompt us to hypothesize that the p53-RNPC loop plays a key role in p53-mediated tumor suppression and longevity, which represents the central hypothesis to be tested in this renewal application. To test this, the following specific aims are proposed: Aim 1 to determine whether Rbm24, a member of the RNPC family, plays a role in the p53 pathway; Aim 2 to determine how phosphorylation modulates RNPC1 to regulate p53 mRNA translation; and Aim 3 to determine whether RNPC1 plays a role in tumor suppression and premature aging in a p53-dependent manner.

? DESCRIPTION (provided by applicant) p63 is a p53 family tumor suppressor. When p63 is expressed from the P1 promoter, five TAp63 isoforms ??????????????? are produced. When p63 is expressed from theP2 promoter, five ?Np63 isoforms are produced. While the transcripts for ten p63 isoforms can be detected by RT-PCR, only proteins for p63? and p63? are found to be detectable and thus the focus of the study. TAp63 contains an N- terminal activation domain conserved in p53 and regulates an array of genes for growth suppression. Indeed, mice deficient in TAp63 are prone to spontaneous tumors and premature aging. In contrast, ?Np63, which contains a unique N-terminal activation domain, is required for proper development of epidermis and other stratified epithelial cells. Additionally, ?Np63 is overexpressed in cancer and classified as an oncoprotein. Rbm38, also called RNPC1, is a RNA-binding protein with one RNA recognition motif (RRM) and a target of p63. Interestingly, we found that Rbm38 inhibits p63? mRNA stability via binding to p63 3' untranslated region (3'UTR). Thus, the mutual regulation between p63 and Rbm38 prompts us to hypothesize that the p63-Rbm38 loop plays a key role in p63-dependent tumor suppression and longevity. The hypothesis will be tested in the following three specific aims: (1) to determine how p63? and p63? are differentially regulated by Rbm38; (2) to determine whether Rbm38 regulates TAp63- and p63?-dependent premature aging and tumor suppression; (3) to determine how the p63-Rbm38 loop is regulated and its biological significance.

PROGRAM SUMMARY/ABSTRACT The Comparative Oncology Program within the UC Davis Comprehensive Cancer Center has evolved and expanded since 2007 from the original Cancer Biology in Animals Program established in 2001. The program focuses on three specific aspects of comparative oncology. The first theme, Tumor Biology, is the study of major oncogenes, tumor suppressor genes, stem cells and inflammation in the context of cancer. The second theme, Genetically Defined Mouse Models of Cancer, employs transgenic and knockout mouse models to elucidate basic mechanisms of tumorigenesis and tumor progression. The third theme, Spontaneous Cancers in Large Animals, uses non-rodent animals to study tumor development and investigate novel therapeutics in a preclinical setting. This program brings a unique combination of skills and models to the preclinical setting. It provides the critical links between the bench and the bedside. The programmatic goals are: 1. To elucidate the molecular and cellular mechanisms by which oncogenes, tumor suppressor genes, stem cells, and inflammation are involved in tumor initiation, progression, and metastasis. 2. To translate fundamental knowledge of tumor biology to trials in companion animal patients and human patients. 3. To educate and train the next generation of investigators in oncology and veterinary oncology at UC Davis. PROGRAM ASPECTS Co-leaders: Xinbin Chen, DVM, PhD, Michael Kent, DVM, Thomas Semrad, MD, MAS Members: 35 Total Grant Funding (ADC): $9.5 million Total Peer-Reviewed Funding (ADC): $8.7 million Total NCI funding (ADC): $2.6 million Total No. Publications: 723 Inter-programmatic publications: 226 (31%) Intra-programmatic publications: 94 (13%) Multi-institutional publications: 342 (47%) The program consists of 35 members from 14 different departments and 4 schools at UC Davis. These members all have research activity in tumor biology and at least one of the other two scientific themes. All of the members are funded, thirty of whom have funding through NCI, NIH, DOD, or other federal and private funding agencies. In FY 2014-2015, the program has total peer reviewed funding (ADC) of $9.5 million, including $2.6 million of NCI funding. The NCI funding ($2.6M) remains stable compared to that in 2011 ($2.6M), suggesting that cancer-focused research remains strong in the program. The program faculty published 723 articles: 31% inter-programmatic and 13% intra-programmatic, indicating that the Program 2 faculty are highly collaborative and conduct trans-disciplinary research.

Project Summary The p53 family of tumor suppressors is consisted of p53, p63, and p73. The p53 family proteins act as a tumor suppressor primarily through their transcriptional targets. We and others showed that ferredoxin reductase (FDXR) is induced directly by p53, p63 and p73. Initial investigations showed that ectopic expression of FDXR increases, whereas partial disruption of the FDXR gene decreases, the sensitivity of tumor cells to DNA damage-induced apoptosis in a p53-dependent manner. To investigate the biological function of FDXR, we carried out a pilot study by generating FDXR-deficient cells and mouse models. We showed that FDXR deficiency promotes iron regulatory protein 2 (IRP2) expression. We also showed that cells deficient in FDXR exhibit iron overload in the mitochondria. Most interestingly, we showed that cells deficient in FDXR are also deficient in p53 and p73 expression. In contrast, p63 expression is increased in FDXR-deficient cells. Furthermore, FDXR+/- mice have a short lifespan along with high incidence of spontaneous tumors. These observations prompt us to hypothesize that the FDXR-p53 family pathway is necessary for tumor suppression. To test this, we will determine: (1) how p53 is regulated by FDXR and the role of the FDXR-p53 loop in tumor suppression; (2) how p63 is regulated by FDXR and the role of the FDXR-p63 loop in tumor suppression; (3) how p73 is regulated by FDXR and the role of the FDXR-p73 loop in tumor suppression.

Project Summary/Abstract Preclinical animal models have been the foundation for the development of novel cancer therapies. Historically, this foundation has relied on mouse models. While mouse models are fundamentally important, the models are insufficient and need to be complemented. Companion animals are an important combination of outbred animals that have spontaneous cancer development with an intact immune system and have environmental and epigenetic exposures as humans. Tackling complex cancer research problems should include investigators with broad experience across animal and human species presenting a unique opportunity for DVMs and MDs to have a crucial role in basic to translational research. Veterinarians can strengthen comparative approaches essential to multidisciplinary research accelerating innovative treatments for animals and humans. Medical doctors bring a patient-centered approach linking biology with clinical therapy. Unfortunately, recruiting and retaining biomedical scientists with comparative oncology expertise, especially DVM or MD clinician-scientists, continues to be a challenging issue facing the broader research community. The Comparative Oncology Training Program (T32) will provide an outstanding environment to train predoctoral (DVM/PhD) students and post-DVM or post-MD fellows who are interested in cancer research. To accomplish this goal, Drs. Chen, Kent, and Canter (MPIs) organized a diverse team of twenty-seven UC Davis faculty mentors from the School of Veterinary Medicine, School of Medicine, College of Biological Science, College of Agricultural and Environmental Sciences, and College of Engineering. The faculty mentors are accomplished biomedical investigators with NCI or cancer-related funding. The proposed program will leverage the NCI-designated UC Davis Comprehensive Cancer Center and will be fully integrated into the Center?s cancer education program. The T32 program?s objectives are to: 1) recruit and retain a diverse group of clinician-scientists that prepares them to become future leaders in academia, government service and public health, 2) expose the T32 scholars to cancer-focused career paths, and 3) train the scholars to use comparative medicine to address human cancer biology. The objectives will be accomplished by providing up to 3-year funding support for DVM/PhD dual-degree predoctoral students and post-DVM or post-MD postdoctoral fellows. During the training, the T32 scholars will enhance their knowledge through tailored coursework, mentored research, multidisciplinary interactions, and career development activities. By the end of the grant period, we expect to train eleven professionals encompassing two dual-degree DVM/PhD students, seven post-DVM fellows, and two post-MD fellows to become highly-qualified basic and translational comparative oncology researchers.

Project Summary/Abstract A clear need to train and retain veterinary physician scientists is outlined by several National Research Council reports in 2004, 2005 and 2013 and by the National Institutes of Health Physician-Scientist Workforce Report in 2014. Recruitment and retention of highly qualified biomedical scientists, especially clinician-scientists with the DVM degree continues to be one of the most challenging issues facing not only the broader research community, but specifically academic veterinary programs around the country. In response, UC Davis School of Veterinary Medicine initiated the Veterinary Scientist Training Program (VSTP) in 2000 with the first class of VSTP students matriculated in August 2001, which has become the second continuing program in the nation. To date, 30 graduates have completed the VSTP program with dual DVM/PhD. Currently, the VSTP program has 17 students and admitted 3 students to the class entering in 2019. Fourteen of our graduates have gone on to leadership careers in academia, government agencies, and industry. 12 recent graduates are still at the early stage of their post-DVM residency and/or postdoctoral training. Only four graduates (13.3%) have chosen to become small animal practitioners, but one of them has indicated to return to academia. Thus, the percentage of our VSTP graduates who are using their research training is more than 80%. Our mission is to prepare our students with dual DVM-PhD degrees to become compassionate and exceptional veterinarian- scientists engaged in basic and translational research to advance the health of people, animals, and environment. The goal of our VSTP program is to provide an outstanding environment for both clinical and biomedical research training at the nation's top-ranked School of Veterinary Medicine and College of Agriculture and Environmental Sciences along with the University's internationally-recognized strong programs in Biological Sciences, Biomedical Engineering, and Human Medicine. Most of our training faculty participate in established Centers and Institutes that promote collaborations and employ diverse evidence-based approaches to solving scientific problems through state-of-the-art equipment in individual labs and campus shared facilities. Our VSTP program hosts a number of student-centered activities, some of which are jointly organized with our medical school MD/PhD program, to create a unique learning environment in comparative medicine. Our students are an integral part of this dynamic environment and promote the excellence of the program through their research, outreach and student mentoring. Our objectives and intended outcomes for this T32 training grant are to: 1) prepare all of our trainees to become future leaders in academia, government service and public health, 2) provide greater exposure to career paths outside academia, 3) maintain the average time (8 years) to degree, 4) attract and train a diverse group of dual degree students, and 5) increase the number of dual degree trainees in training at UC Davis from 17 to 24.