BACTERIA AND LYMPHOCYTE SUPPRESSION IN PERIODONTITIS

牙周炎中的细菌和淋巴细胞抑制

• 批准号: 7807606
• 负责人: BRUCE J SHENKER
• 金额: $ 31.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807606
• 关键词: 1-Phosphatidylinositol 3-Kinase; Amino Acids; Apoptosis; Area; Award; Bacteria; Binding; CC chemokine receptor 4; CCL17 gene; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell membrane; Cell surface; Cells; Chimeric Proteins; Cholera Toxin; Cholesterol; Consensus Sequence; Cutaneous; Defect; Dental Schools; Deoxyribonuclease I; EGF gene; Employee; Employment Opportunities; Endocytosis; Epidermal Growth Factor Receptor; Event; Exhibits; Faculty; Fc Receptor; Fluorescence; Funding; Fusion Toxin; Future; Genes; Growth; Guidelines; Head and neck structure; Human Resources; Immunosuppressive Agents; Immunotoxins; Inhibition of Cell Proliferation; Intervention; Investigation; Lead; Lecithin; Link; Lipids; Lymphocyte; Lymphocyte Suppression; Lymphoid Cell; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Medicine; Membrane Lipids; Membrane Microdomains; Molecular; Mutation; New Jersey; Occupations; Organism; Parents; Pathway interactions; Patients; Pennsylvania; Periodontitis; Philadelphia; Phosphatidylinositols; Phospholipase C; Phospholipase D; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Positioning Attribute; Postdoctoral Fellow; Protein Kinase C; Proteins; Recovery; Recruitment Activity; Request for Applications; Research; Research Support; Role; Schools; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingomyelins; Squamous cell carcinoma; Structure; Surface; Surface Plasmon Resonance; T-Cell Lymphoma; Targeted Toxins; Testing; Therapeutic Agents; Time; Toxic effect; Toxin; Toxin Conjugates; Transmembrane Domain; Universities; Virulence Factors; Wages; X-Ray Crystallography; base; cancer cell; cancer type; cell growth; cellugyrin; chemokine; college; cytokine; cytolethal distending toxin; economic impact; experience; fluorescence activated cell sorter device; holotoxins; human PHEMX protein; meetings; microbial; mouth squamous cell carcinoma; neoplastic cell; novel; novel therapeutic intervention; overexpression; parent grant; phosphatidylcholine-specific phospholipase C; public health relevance; receptor; research study; trafficking; tripolyphosphate

DESCRIPTION (provided by applicant): The University of Pennsylvania contributes substantially to the Southeastern Pennsylvania and New Jersey economy. The University employs 22,000 scientists and research support personnel. Moreover, in 2008 Penn scientists were the recipient of over $800 million in total research awards; it is estimated that these awards had an economic impact on the Philadelphia region equivalent to $3.15 billion. The School of Dental Medicine is an important component of this economic impact; thus far in 2009, SDM scientists have been the recipient of >$48 million in total research awards. Moreover, the School contributes >$40 million to the region in salary, employee benefits and purchases. Additionally, the SDM employs over 260 faculty, 60 in full time positions, and the equivalent of 434 full time equivalent support staff. The current proposal will create or retain two skilled jobs at the level of research technician and/or postdoctoral research fellow. Cancer cells escape normal growth control as a consequence of activating mutations or increased expressionofcellularprotooncogenesand/orinactivatingmutationsordecreasedexpressionoftumorsuppressor genes. It is evident that the phosphoinositide 3-kinase (PI-3K)/PI-3,4,5-P3/PTEN/Akt) signaling pathway is often altered in cancer making it a potent target for pharmacologic intervention. Regardless of whether the defect in this pathway involves synthesis or degradation, PI3,4,5-P3 elevations lead to activation of pAkt and downstream signals that favor growth, proliferation and survival. During the current funding period of the parent grant, we demonstrated the active subunit of the cytolethal distending toxin, CdtB, functions as a PI-3,4,5-P3 phosphatase. We propose to extend our observations in a new direction and begin to harness the pharmacologic potential of this microbial toxin. In this competitive supplement, we plan to generate novel chimeric fusion toxins which target PI-3,4,5-P3 to block cell proliferation and survival of malignant cells derived from cutaneous T-cell lymphoma (CTCL) patients or patients with head, neck and oral squamous cell carcinoma (SCC). We propose to generate chimeric fusion toxins that target either CTCL or to SCC and test the hypothesis that the toxins retain PI-3,4,5-P3 phosphatase activity and specifically bind to and intoxicate CTCL cells that over-express CCR4 or SCC cells that over-express EGFR. CdtB will be chemically linked to anti-receptor antibodies which are commercially available or genetically linked to cytokines, TARC or EGF, to also target the chimeric toxin to CCR4 and EGFR, respectively. The chimeric toxins will be evaluated for PI-3,4,5P3-phosphatase activity, capacity to bind to tumor cells and deliver CdtB intracellularly and for toxicity. Significance: The studies described in this proposal extend our current investigation on the role of Cdt as a putative virulence factor to a consideration of its utility as a potential therapeutic agent for treating certain types of cancer with defects in the PI-3K/PIP3/Akt signaling pathway. These studies are significant in that they will provide the underpinnings for a novel therapeutic approach to treat cancers such as CTCL and SCC. PUBLIC HEALTH RELEVANCE: The active subunit of the bacterial cytolethal distending toxin, CdtB, exhibits a novel enzymatic activity that targets a mediator of a critical signaling pathway that controls cell growth and survival. We propose to take advantage of this unique activity and develop fusion proteins that will potentially target tumor cells resulting in growth arrest and ultimately cell death. These studies are significant in that they will provide the underpinnings on which to base future novel therapeutic approaches to treat certain forms of cancer.

描述（由申请人提供）：宾夕法尼亚大学为宾夕法尼亚州东南部和新泽西州的经济做出了重大贡献。该大学雇用22,000名科学家和研究支持人员。此外，在2008年，宾夕法尼亚州科学家获得了超过8亿美元的研究奖；据估计，这些奖项对费城地区的经济影响相当于31.5亿美元。牙科医学学院是这种经济影响的重要组成部分；到目前为止，2009年，SDM科学家在总研究奖中获得了超过4800万美元的奖金。此外，学校以薪水，员工福利和购买为该地区捐款超过4000万美元。此外，SDM拥有260多名教职员工，60名全职职位，相当于434名全职同等支持人员。当前的建议将在研究技术员和/或博士后研究员的水平上创建或保留两个熟练的工作。 癌细胞由于激活突变或表达增加而逃脱了正常的生长控制。显然，磷酸肌醇3-激酶（PI-3K）/PI-3,4,5-P3/PTEN/AKT）信号传导途径通常会在癌症中改变，从而使其成为药理干预的有效靶标。不管该途径中的缺陷是否涉及合成或降解，PI3,4,5-P3升高会导致PAKT和下游信号激活，这些信号有利于生长，增殖和生存。在父授予赠款的当前资金期间，我们证明了细胞降低的毒素，CDTB的活性亚基，作为PI-3,4,5,4,5-P3磷酸酶。我们建议将观察结果扩展到一个新的方向，并开始利用这种微生物毒素的药理潜力。在这种竞争性补充剂中，我们计划产生新型的嵌合融合毒素，靶向PI-3,4,5-P3，以阻止来自皮肤T细胞淋巴瘤（CTCL）患者或头部，颈部和口服鳞状细胞癌（SCC）患者的恶性细胞的细胞增殖和生存。我们建议生成靶向CTCL或SCC的嵌合融合毒素，并检验以下假设：毒素保留PI-3,4,5-P3磷酸酶活性，并特异性结合并与过表达CCR4或SCC细胞过表达EGFR的CCR4或SCC细胞。 CDTB将在化学上与抗受体抗体有关，这些抗体抗体分别与细胞因子TARC或EGF遗传有关，分别将嵌合毒素靶向CCR4和EGFR。将评估嵌合毒素的PI-3,4,53-磷酸酶活性，与肿瘤细胞结合并细胞内和毒性递送CDTB的能力。意义：该提案中描述的研究将我们当前对CDT作为推定毒力因子的作用的研究扩展到将其用作效用作为一种潜在的治疗剂，用于治疗某些类型的癌症，在PI-3K/PIP3/AKT信号通路中存在缺陷。这些研究很重要，因为它们将为治疗CTCL和SCC等新型治疗方法提供基础。 公共卫生相关性：细菌细胞降低毒素CDTB的活性亚基表现出一种新型的酶促活性，该活性针对了控制细胞生长和存活的临界信号通路的介体。我们建议利用这种独特的活性并发展融合蛋白，该蛋白可能靶向肿瘤细胞，从而导致生长停滞并最终导致细胞死亡。这些研究很重要，因为它们将提供基于未来新型治疗方法来治疗某些形式的癌症的基础。