Michael J. Schell - US grants

The aim of this research is to understand the roles of inositol polyphosphates and their specific binding proteins in controlling the homestasis of calcium in brain. It is known that brief excitotoxic insults to hippocampal pyramidal cells causes their demise, but only days after the insult. This observation raises the possibility that medical treatments might be developed which could be administered after a stroke, seizure, or heart attack to reduce the subsequent delayed neuronal damage. The biochemical events occurring between the insult and the death are not understood, but involve aberrations in calcium homeostasis. The proposed experiments will use fluorescent imaging to examine normal and pathological calcium dynamics in cultured neuronal and glial cells. To understand the molecular mechanisms underlying the responses, the focus will b GAP1IP4BP, an inositol tetrakisphosphate (IP4) binding protein that interacts with the Ras signalling pathway. This protein lies at a crucial branch point in cellular signalling and may link the changes in intracellular calcium after toxic insuts to the subsequent death of neurons. Initial studies will establish expression levels of GAP1IP4BP and IP4 levels in the cultured cells. Neurons and glia will then be microinjected with blockers and stimulators of the GAP1IP4BP signal transduction pathways, and the spatiotemporal changes in intracellular calcium dynamics will be visualized in individual cells. Once the normal calcium response neurons is characterized, the cells will be exposed to excitotoxic insults and then injected with various molecular probes of the IP4 signal transduction pathways in an attempt to modify the calcium dynamics.

The goal of the Biostatistics and Data Management Core Facility is to provide statistical analytic collaboration and data management support members of the UNC Lineberger Comprehensive Cancer Center. Biostatistical services include research/protocol design and data analysis for clinical trials, and for epidemiologic, cancer prevention and control, and basic science studies. Data management services involve the development, integration, and management of cancer research data, particularly patient-related data. The Core is led by Drs. Michael Schell and Joseph Ibrahim. The Core adds value to the Center by providing critical analytic and data management support to the key research activities of the Cancer Center. Highlights of research supported by the Core include LCCC 9719, a 230-patient multi-center clinical trial of advanced stage lung cancer (PI: Dr. Mark Socinski), and the identification of a target recall rate for mammographers (PI: Dr. Bonnie Yankaskas). Over the past five years, the use of the Facility has grown. During the past year, a data management group has been added to the Facility, and a major database effort has been launched. Future plans for the Core include recruitment of a second full-time faculty biostatistician, further integration of Biostatistics and Statistics faculty on specific research problems requiring specialized expertise, and continued development of an integrated database system.

[unreadable] DESCRIPTION (provided by applicant): Tumor hypoxia plays an important role in the malignant progression and clinical outcome of solid cancers. This may be because tumor hypoxia induces the expression of angiogenic and cell survival-promoting cytokines and enhances invasiveness of cancer cells. We have recently provided evidence for hypoxia-inducible autocrine erythropoietin (Epo) signaling in the malignant progression of several human cancers including breast, cervical, endometrial, and head/neck cancer. Epo and the Epo receptor (EpoR), are among many genes upregulated by tumor hypoxia, and Epo signaling promotes invasiveness of head/neck cancer cells. The transcription factor known as hypoxia-inducible factor-1 (HIF-1) is critically involved in tumor hypoxia induced adaptations. Expression of HIF-1 alpha, the key hypoxia-regulated subunit of HIF-1, is highly up-regulated in a variety of human cancers and is strongly correlated with tumor grade, angiogenesis, and adverse clinical outcome. We have discovered a novel hypoxia-independent mechanism that increases HIF-1 alpha levels in cancer cells via the glycolytic metabolite pyruvate. We have also discovered that ascorbate and specific amino acids can reverse this process. The goal of this application is to determine whether lowering basal HIF-1 expression by using ascorbate and amino acids can reduce HIF-induced gene expression, Epo signaling, and invasiveness of human head/neck cancer cells. We will also determine whether in vivo treatment with ascorbate and amino acids can lower HIF-1 expression, Epo and EpoR expression, and tumor growth in a human head/neck cancer xenograft model. We believe that our studies will yield novel and safe therapeutic options for cancer patients. [unreadable] [unreadable]

Biostatistics Core B will provide collaborative analytic support to all 4 Moffitt Skin SPORE projects, the other 2 Cores, and the Developmental Research and Career Development Programs. Each project has a faculty biostatistician, selected to maximize the link between their applied research focus and the project. There, will be 4 clinical trials, including phase 1 trials in Projects 2 and 3 that will use a modified Ji design, chosen to provide a richer experience in establishing an MTD. This design, which received extensive discussion and included some modification by the Core B statisticians, will receive special ongoing attention as befits a novel analytical approach. Projects 2 and 4 are both very involved from an analytical perspective and will receive the highest proportions of funding. Project 2 involves extensive proteomics analyses and uses a multi-level Bayesian model developed in part by the project 2 statistician. Project 4 is a case-cohort study involving 1500 participants and 3,000 person-years of follow-up, and includes numerous demographic and lifestyle factors to be examined. In conjunction with Cores A and C, this core will play a vital role in SPORE database development, especially with the clinical trials and case-cohort studies. Biostatistics Core B will be involved in the development of all proposed Developmental Research and Career Development Programs, and will provide analytic support to those that are funded. Working under the direction of faculty biostatisticians are two staff statisticians, who will handle a significant share of the direct statistical programming needed.

PROJECT SUMMARY The overall goal of the Biostatistics Core (BC) is to provide statistical design and analysis expertise supporting the research efforts of Moffitt Cancer Center (MCC) members. Service begins with analytical design and determination of sample size (e.g., grant and clinical trial submissions), leading to project conduct, monitoring of accumulating research data on active projects, and manuscript development. The BC provides key quantitative analytical results, including tables, figures, and scientific conclusions. Faculty biostatisticians provide education and training in biostatistics, participate actively in the Scientific Review Committees (SRC) and Protocol Review & Monitoring Committee (PRMC), and serve as reviewers for internal grant applications. The BC's Specific Aims are to: 1) Support members by providing high-quality biostatistical design and analysis services; 2) Educate and train investigators on biostatistical resources and tools; and 3) Develop and implement methods for state-of-the-art statistical analyses. The BC also supports the conduct of research through involvement on various oversight committees (e.g., SRC and PRMC). The BC includes nine faculty, seven staff biostatisticians, a Core Facility Manager and a Project Manager. Faculty biostatisticians dedicate 50% to 60% of their effort to the BC and are supported by grant funding, revenue from clinical trials, and institutional support. Staff biostatisticians and the Core Facility Manager are dedicated to the BC and are supported by chargebacks, revenue from clinical trials, and institutional support. BC faculty and staff are involved at all stages of scientific research, from study design to publication of research findings. Most BC efforts involve BC faculty-staff teams. During the past funding cycle, the BC played significant roles in both the Lung and Skin SPORE grants. In addition, BC biostatisticians are part of every investigator-initiated therapeutic clinical trial conducted at MCC. Over the past five years, the BC has supported over 500 clinical trials, research efforts across all five research programs, and research projects that have received SRC approval. In the most recent fiscal year, the BC supported 78 members, with 75% of usage for peer-reviewed-funded members. There are two BC faculty members on each of four SRCs and the PRMC.