The role of platelets in tumor growth, wound healing and other angiogenesis disea

血小板在肿瘤生长、伤口愈合和其他血管生成疾病中的作用

• 批准号: 8307637
• 负责人: Giannoula Lakka Klement
• 金额: $ 32.78万
• 依托单位: GENESYS RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307637
• 关键词: role; platelets; tumor; growth; wound

DESCRIPTION (provided by applicant): The role of platelets in tumor growth, wound healing and other angiogenesis disease states The role of platelets in angiogenesis has been appreciated in the past both clinically and pre- clinically. We have recently published evidence that platelets actively sequester angiogenesis stimulators as well as inhibitors, and that there may be a higher organization of these opposing roles within platelet. This higher organization may facilitate the ability of platelets to modify angiogenesis in many angiogenesis-dependent disorders such as wound healing, atherosclerosis, tumor growth, macular degeneration and many others. Since the ability of platelets to enhance wound healing is restricted to intact platelets and does not extend to previously frozen platelets, the process most likely involves a reciprocal interaction between live, fully functional platelet and the wound microenvironment. Unlike other cells, platelets are destroyed by freezing. This proposal will a) characterize the molecular and cellular mechanisms by which platelets sequester and store angiogenesis regulators (Specific Aim 1); b) evaluate the mechanisms of release of these angiogenesis regulators from platelets (Specific Aim 2); c) test the potential therapeutic relevance of strategies designed to selectively release stimulators or inhibitors of angiogenesis from platelets in wound and tumor models (Specific Aim 3). The goal of these studies will be to provide a framework for development of novel targeted therapies for improvement of wound care, as well as for inhibition of tumor growth. It is expected that many agents that modify platelet function, secretion of proteins from platelets, and/or platelet adhesion will be applicable for management pathologic angiogenesis. PUBLIC HEALTH RELEVANCE: Platelets are very important in the formation of the provisional matrix that facilitates the growth of new vessels. This process is evident during physiological angiogenesis (such as wound healing or ovulation), as well as in pathological angiogenesis (such as tumor growth, arthritis, endometriosis, macular degeneration, retinopathy etc.). Exploring the similarities of these processes could be therefore very informative. As we have recently demonstrated, the ability of platelets to up- or down-regulate angiogenesis depending on the tissue needs is attributable to a higher organization of stimulators and inhibitors of angiogenesis within platelets. An improved understanding about this ability to down- regulate angiogenesis during wound healing or about the continued stimulation of angiogenesis in tumor growth is likely to lead to novel therapeutic targets. The immediate goal of our initiative will therefore be to improve the knowledge about the basic mechanisms of platelet-facilitated modulation of angiogenesis in wound healing and tumor growth. The anticipated benefit is that our efforts will lead to discovery of unique molecular targets that could then be studied in clinical trials, and lead to an accelerated improvement in the lives of children and adults, who face death from cancer, or disability due to chronic wounds.

描述（由申请人提供）：血小板在肿瘤生长、伤口愈合和其他血管生成疾病状态中的作用血小板在血管生成中的作用在过去的临床和临床前已被认识到。我们最近发表的证据表明，血小板主动隔离血管生成刺激剂和抑制剂，并且血小板内可能存在更高的这些相反作用的组织。这种高级组织可能会促进血小板在许多血管生成依赖性疾病中改变血管生成的能力，例如伤口愈合、动脉粥样硬化、肿瘤生长、黄斑变性等。由于血小板促进伤口愈合的能力仅限于完整的血小板，并且不能扩展到先前冷冻的血小板，因此该过程很可能涉及活的、功能齐全的血小板与伤口微环境之间的相互作用。与其他细胞不同，血小板会被冷冻破坏。该提案将 a) 描述血小板隔离和储存血管生成调节剂的分子和细胞机制（具体目标 1）； b) 评估血小板释放这些血管生成调节剂的机制（具体目标 2）； c) 测试旨在从伤口和肿瘤模型中的血小板选择性释放血管生成刺激剂或抑制剂的策略的潜在治疗相关性（具体目标 3）。这些研究的目标是为开发新型靶向疗法提供框架，以改善伤口护理以及抑制肿瘤生长。预期改变血小板功能、血小板蛋白质分泌和/或血小板粘附的许多药剂将适用于控制病理性血管生成。 公共卫生相关性：血小板对于促进新血管生长的临时基质的形成非常重要。这一过程在生理性血管生成（如伤口愈合或排卵）以及病理性血管生成（如肿瘤生长、关节炎、子宫内膜异位症、黄斑变性、视网膜病变等）中都很明显。因此，探索这些过程的相似性可能会提供很多信息。正如我们最近所证明的，血小板根据组织需求上调或下调血管生成的能力可归因于血小板内血管生成的刺激剂和抑制剂的更高组织。对这种在伤口愈合过程中下调血管生成的能力或对肿瘤生长中持续刺激血管生成的能力的进一步了解可能会带来新的治疗靶点。因此，我们计划的直接目标是提高对伤口愈合和肿瘤生长中血小板促进的血管生成调节基本机制的了解。预期的好处是，我们的努力将导致发现独特的分子靶标，然后在临床试验中进行研究，并加速改善面临癌症死亡或慢性伤口致残的儿童和成人的生活。