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）：宾夕法尼亚大学对宾夕法尼亚州东南部和新泽西州的经济做出了重大贡献。该大学拥有 22,000 名科学家和研究支持人员。此外，2008 年，宾夕法尼亚大学的科学家获得了总计超过 8 亿美元的研究奖项；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。牙科医学院是这种经济影响的重要组成部分； 2009年迄今为止，SDM科学家已获得总计超过4800万美元的研究奖项。此外，学院在工资、员工福利和采购方面为该地区贡献了超过 4000 万美元。此外，SDM 还雇用了 260 多名教职员工，其中 60 名全职员工，以及 434 名全职支持人员。目前的提案将创造或保留两个研究技术员和/或博士后研究员级别的技术岗位。 由于细胞原癌基因的激活突变或表达增加和/或肿瘤抑制基因的失活突变或表达减少，癌细胞逃脱了正常的生长控制。很明显，磷酸肌醇 3-激酶 (PI-3K)/PI-3,4,5-P3/PTEN/Akt）信号通路在癌症中经常发生改变，使其成为药物干预的有效靶点。无论该途径中的缺陷是否涉及合成或降解，PI3,4,5-P3 升高都会导致 pAkt 和有利于生长、增殖和存活的下游信号激活。在当前资助期间，我们证明了细胞致死膨胀毒素 CdtB 的活性亚基具有 PI-3,4,5-P3 磷酸酶的功能。我们建议将我们的观察扩展到一个新的方向，并开始利用这种微生物毒素的药理学潜力。在这一竞争性补充剂中，我们计划生产新型嵌合融合毒素，以 PI-3,4,5-P3 为靶点，阻止来自皮肤 T 细胞淋巴瘤 (CTCL) 患者或头颈和口腔鳞状细胞癌 (SCC) 患者的恶性细胞的增殖和存活。我们建议生成针对 CTCL 或 SCC 的嵌合融合毒素，并测试以下假设：这些毒素保留 PI-3,4,5-P3 磷酸酶活性，并特异性结合并中毒过度表达 CCR4 的 CTCL 细胞或过度表达 EGFR 的 SCC 细胞。 CdtB将与市售的抗受体抗体化学连接，或与细胞因子、TARC或EGF基因连接，以分别将嵌合毒素靶向CCR4和EGFR。将评估嵌合毒素的 PI-3,4,5P3-磷酸酶活性、与肿瘤细胞结合和在细胞内递送 CdtB 的能力以及毒性。意义：本提案中描述的研究将我们目前对 Cdt 作为假定毒力因子的作用的研究延伸到考虑其作为潜在治疗剂的用途，用于治疗具有 PI-3K/PIP3/Akt 信号通路缺陷的某些类型的癌症。这些研究意义重大，因为它们将为治疗 CTCL 和 SCC 等癌症的新治疗方法提供基础。 公共健康相关性：细菌细胞致死膨胀毒素 CdtB 的活性亚基表现出一种新型酶活性，其目标是控制细胞生长和存活的关键信号传导途径的介质。我们建议利用这种独特的活性，开发可能靶向肿瘤细胞的融合蛋白，导致生长停滞并最终导致细胞死亡。这些研究的意义重大，因为它们将为未来治疗某些形式的癌症的新治疗方法提供基础。