Complement in Cell Proliferation and Injury-Therapeutic Interventions

细胞增殖和损伤治疗干预中的补充

• 批准号: 7298797
• 负责人: JOHN D LAMBRIS
• 金额: $ 119.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298797
• 关键词: Complement; Cell; Proliferation; Injury; Therapeutic

DESCRIPTION (provided by applicant): This is an application for an integrative research effort to understand and define the mechanisms by which complement exerts its biological functions in models of ovarian cancer and in processes of tissue regeneration and cell injury. The molecular and cellular basis of complement activity in these settings is not yet fully understood. The proposed Program will clarify this by bringing together investigators with profound expertise in different fields of complement biology, who share the same appreciation for the complexity of the system and are committed to addressing and elucidating the basic mechanisms that underlie these complement-modulated processes. Each laboratory involved has developed well-defined model systems that will allow the dissection of the critical components and mechanisms by which the complement system participates in cell survival or disease pathogenesis. The laboratory of Dr. Lambris will investigate the role of complement in liver regeneration. Well-established models of partial hepatectomy and toxic liver injury using various complement system knockout mice will clarify this. The laboratory of Dr. Coukos will investigate the role of the complement system in ovarian cancer. The role of the complement components and receptors will be analyzed using a transgenic ovarian cancer model. To modulate complement mediated cell proliferation during liver regeneration and cancer development or tissue damage associated with toxic liver injury, the laboratory of Dr. Lambris will further optimize existing therapeutics and design novel ones. His laboratory will develop and characterize specific inhibitors of complement activation and function, and compare their efficacy in the experimental in vivo models. The combined effort of the laboratories involved will elucidate the convergences of mechanisms by which complement exerts its functions in tumor initiation and growth versus tissue regeneration in order to identify suitable therapeutic targets in both settings. The principal investigators involved with these projects have a long history of scientific interaction that they wish to maintain and expand through the successful funding of this application. PROJECT 1: COMPLEMENT AND CYTOKINE NETWORK IN LIVER REGENERATION, Lambris. J PROJECT 1 DESCRIPTION (provided by applicant): The unusual regenerative properties of the liver have evolved as an efficient adaptation that allows this organ to cope with many hazardous conditions, including alcoholism, drug overdose, and viral hepatitis. Recent studies in our laboratory have demonstrated the involvement of complement in the priming phase of liver regeneration. The regenerative response is impaired after partial hepatectomy (PHx) and carbon tetrachloride (CCI4) injury in several mouse strains deficient in complement components. Impairment of regeneration has been demonstrated by a decreased and delayed replication rate of liver cells. Moreover, complement deficiencies have been associated with significant injury to the liver parenchyma after PHx. Our recent data indicate that complement deficiency alters the cytokine milieu after PHx, including cytokines essential for liver cell proliferation and survival. Therefore, we hypothesize that complement proteins are involved in the regulation of two cellular processes crucial for successful regeneration: proliferation of liver cells and hepatoprotection. The current research proposal aspires to elucidate the role of complement components in cell proliferation and survival using the PHx model, and to determine the effect of therapeutic interventions involving the complement system on tissue injury induced by CCI4. The studies in Aim 1 are designed to define the role of individual complement components in cell proliferation and hepatoprotection after PHx. This goal will be achieved by disrupting complement signaling pathways after PHx using mice deficient in various complement components, then monitoring liver cell proliferation and injury. The studies in Aim 2 will dissect the mechanisms by which complement components influence liver cell proliferation and survival after PHx. The serum levels of cytokines known to be essential for liver cell proliferation and survival, together with their downstream targets in the liver, will be analyzed in mice deficient in complement proteins. ? In addition, the role of anaphylatoxins in liver regeneration-associated angiogenesis will be investigated. ?? Finally, the research described in Aim 3 is designed to ascertain whether therapeutic interventions involving the complement system will decrease the magnitude of tissue injury resulting from CCI4-mediated toxicity. The proposed studies should lead to a better understanding of the relationship between regulatory molecules of inflammation and cell proliferation and death, two cellular processes essential for physiology and pathology.

描述（由申请人提供）：这是一项综合研究工作的申请，旨在了解和定义补体在卵巢癌模型以及组织再生和细胞损伤过程中发挥其生物学功能的机制。在这些环境中补体活性的分子和细胞基础尚未完全理解。拟议的计划将通过汇集在补体生物学不同领域具有深厚专业知识的研究人员来澄清这一点，他们对系统的复杂性有着相同的认识，并致力于解决和阐明这些补体调节过程的基本机制。每个参与的实验室都开发了定义明确的模型系统，这些系统将允许对补体系统参与细胞存活或疾病发病机制的关键组分和机制进行解剖。Lambris博士的实验室将研究补体在肝再生中的作用。使用各种补体系统敲除小鼠建立的部分肝切除术和毒性肝损伤模型将阐明这一点。Coukos博士的实验室将研究补体系统在卵巢癌中的作用。将使用转基因卵巢癌模型分析补体成分和受体的作用。为了在肝再生和癌症发展或与毒性肝损伤相关的组织损伤期间调节补体介导的细胞增殖，Lambris博士的实验室将进一步优化现有的治疗方法并设计新的治疗方法。他的实验室将开发和表征补体激活和功能的特异性抑制剂，并比较它们在实验体内模型中的功效。所涉及的实验室的共同努力将阐明补体在肿瘤起始和生长与组织再生中发挥其功能的机制的趋同性，以便在两种情况下确定合适的治疗靶点。参与这些项目的主要研究人员有着悠久的科学互动历史，他们希望通过成功资助这项申请来保持和扩大这种互动。 项目1：肝脏再生中的补体和细胞因子网络，Lambris。J 项目1描述（由申请人提供）：肝脏不寻常的再生特性已经发展成为一种有效的适应，使该器官能够科普许多危险情况，包括酗酒，药物过量和病毒性肝炎。我们实验室最近的研究表明，补体参与了肝再生的启动阶段。部分肝切除术（PHx）和四氯化碳（CCI4）损伤后，在几个小鼠品系缺乏补体成分的再生反应受损。肝细胞复制率降低和延迟已证明再生受损。此外，补体缺乏与PHx后肝实质的显著损伤相关。我们最近的数据表明，补体缺乏改变PHx后的细胞因子环境，包括肝细胞增殖和存活所必需的细胞因子。因此，我们假设补体蛋白参与调节两个对成功再生至关重要的细胞过程：肝细胞增殖和肝保护。目前的研究计划旨在阐明补体成分在PHx模型中细胞增殖和存活中的作用，并确定涉及补体系统的治疗干预对CCI4诱导的组织损伤的影响。目的1中的研究旨在确定单个补体成分在PHx后细胞增殖和肝保护中的作用。这一目标将通过使用缺乏各种补体成分的小鼠在PHx后破坏补体信号传导途径来实现，然后监测肝细胞增殖和损伤。目的2中的研究将剖析补体成分影响PHx后肝细胞增殖和存活的机制。将在补体蛋白缺乏的小鼠中分析已知对肝细胞增殖和存活至关重要的细胞因子的血清水平及其在肝脏中的下游靶点。?此外，过敏毒素在肝再生相关血管生成中的作用也将被研究。??最后，目的3中描述的研究旨在确定涉及补体系统的治疗干预是否会降低由CCl 4介导的毒性引起的组织损伤的程度。拟议的研究应导致更好地理解炎症和细胞增殖和死亡的调节分子之间的关系，这两个细胞过程对生理学和病理学至关重要。