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CAREER: Modulating Local Tumor Hypoxia using Cryogel Scaffolds to Regulate Dendritic Cell Function and Activity

职业：使用 Cryogel 支架调节局部肿瘤缺氧，调节树突状细胞功能和活性

基本信息

批准号：
1847843
负责人：
SIDI BENCHERIF
金额：
$ 62万
依托单位：
Northeastern University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1847843&HistoricalAwards=false
关键词：
CAREER Modulating Local Tumor Hypoxia

项目摘要

Non-technical AbstractHypoxia is an abnormal decrease of oxygen levels in tissues. Although different tissues and cells have distinct thresholds and susceptibility to hypoxia, at a cellular level, hypoxia and hypoxic responses generally occur at approximately 1-3 % oxygen. Compelling evidence has shown that reduced tissue oxygenation is present in various diseases, and more particularly cancer. A large number of human solid tumors profoundly lack oxygen, exhibiting hypoxic tumor areas; this condition is mainly due to an imbalance between delivery of oxygen via the blood circulation and consumption by cancer cells. Hypoxia can arise via a number of mechanisms. For instance, fast growing hypoxic tumors typically have poor vessel bio-distribution, increased vascular defects, and low vessel number. Furthermore, highly proliferating cancer cells that outgrow the neovascularization also participate in tumor hypoxia. An increasing list of cancers with hypoxic regions has been reported over the last decade and include endometrial carcinoma, ovarian, melanoma, lymphoma, breast, bladder, brain, head and neck, renal, colon, gastric, pancreatic, prostate, and non-small cell lung cancers. The research objective of this proposal is to apply standard methods of biomaterials science and engineering to emulate a hypoxic tumor microenvironment and better understand the interplay between tumor and dendritic cells, the major directors of immune responses. The proposed studies are likely to offer new modalities in cancer immunotherapy and are expected to justify the use of hypoxia-suppressive biomaterials, reinforce tumoricidal functions of immune cells, and ultimately increase tumor rejections. The educational goal of this proposal is to introduce biomaterials science and engineering to high school students (develop hands-on science curriculum, promote practical research experience, and foster STEM field trips to the campus), enhance undergraduate research exposure and experience to underrepresented students (Hispanic, African-American, and female), and expand the Northeastern University co-op model to include graduate and academic lab experiences. Technical AbstractHypoxic cancers are usually aggressive, resistant to standard therapies, and thus very difficult to eradicate. A better understanding of how these hypoxic cancer cells interact with the immune system would allow tailoring of efficient therapies and better outcomes. Hypoxia can inhibit differentiation, antigen capture, maturation, lymph node homing of dendritic cells (DCs), the main regulators of immune responses, which can impair downstream T cell development, differentiation and cytotoxic activity. Immunosuppression represents one of the fundamental tumor immune evasion mechanisms. Therefore, it is important to expand our understanding on how hypoxia affects DCs and find ways to circumvent hypoxia-driven immunosuppression locally and restore immune cell function and activity. To address this need, the primary research objective of this proposal is to engineer biomaterials to modulate the local hypoxic environment to understand immune cell function and activity. To achieve this goal, this proposal has three aims: 1) Design injectable oxygen-generating cryogel scaffolds to controllably deliver oxygen, 2) Engineer a B16-F10 melanoma tumor microenvironment in three-dimension and deliver oxygen locally to modulate inherent and tumor-induced hypoxia, and 3) Disrupt hypoxia and modulate oxygen tension to understand how local oxygenation can regulate dendritic cell survival and function and impact their activity in an in-vitro ovalbumin (B16-F10/OVA) melanoma model. The long-term educational goal of the proposal is to promote and train the next generation of scientists to work in academia, industry and clinical settings developing innovative biomaterials to improve human quality of life. The major aims of this program are: 1) Introduce K-12 students to Biomaterials Science (develop a hands-on science curriculum, implement practical research experience, and foster STEM field trips to campus), 2) Enhance undergraduate research exposure and experience to underrepresented students (Hispanic, African-American, and female), and 3) Expand the Northeastern University co-op model to include graduate and academic lab experiences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术性摘要低氧是指组织中氧气水平的异常下降。虽然不同的组织和细胞对低氧有不同的阈值和敏感性，但在细胞水平上，低氧和低氧反应通常发生在大约1-3%的氧气中。令人信服的证据表明，组织氧合减少存在于各种疾病中，尤其是癌症。大量人体实体肿瘤严重缺氧，呈现肿瘤缺氧区；这种情况主要是由于血液循环中的氧气输送和癌细胞消耗之间的失衡。低氧可通过多种机制发生。例如，快速生长的缺氧性肿瘤通常具有较差的血管生物分布、更多的血管缺陷和较少的血管数量。此外，生长在新生血管之外的高度增殖的癌细胞也参与了肿瘤缺氧。在过去的十年中，有越来越多的低氧区癌症被报道，包括子宫内膜癌、卵巢癌、黑色素瘤、淋巴瘤、乳腺癌、膀胱癌、脑、头颈部、肾癌、结肠癌、胃癌、胰腺癌、前列腺癌和非小细胞肺癌。这项建议的研究目标是应用生物材料科学和工程的标准方法来模拟低氧的肿瘤微环境，并更好地了解肿瘤和树突状细胞之间的相互作用，树突状细胞是免疫反应的主要导向。拟议的研究可能为癌症免疫治疗提供新的方式，并有望证明使用低氧抑制生物材料的合理性，增强免疫细胞的杀瘤功能，并最终增加肿瘤排斥反应。这项提议的教育目标是向高中生介绍生物材料科学和工程(开发动手科学课程，促进实践研究经验，并鼓励STEM到校园进行实地考察)，增加本科生对未被充分代表的学生(西班牙裔、非裔美国人和女性)的研究接触和经验，并将东北大学的合作模式扩展到包括研究生和学术实验室经验。技术摘要缺氧性癌症通常侵袭性强，对标准治疗耐药，因此很难根除。更好地了解这些低氧癌细胞如何与免疫系统相互作用，将有助于定制有效的治疗方法和更好的结果。低氧可抑制免疫应答的主要调节者树突状细胞(DC)的分化、抗原捕获、成熟、淋巴归巢，从而损害下游T细胞的发育、分化和细胞毒活性。免疫抑制是肿瘤免疫逃避的基本机制之一。因此，扩大我们对低氧对DC影响的认识，寻找局部规避低氧诱导的免疫抑制，恢复免疫细胞功能和活性的方法是非常重要的。为了满足这一需求，这项建议的主要研究目标是设计生物材料来调节局部缺氧环境，以了解免疫细胞的功能和活性。为了实现这一目标，这项建议有三个目标：1)设计可注射的产氧冷冻支架，以可控地输送氧气；2)在三维空间设计B16-F10黑色素瘤微环境，并在局部输送氧气以调节固有和肿瘤诱导的缺氧；3)中断缺氧并调节氧分压，以了解在体外卵清蛋白(B16-F10/OVA)黑色素瘤模型中，局部充氧如何调节树突状细胞的生存和功能以及影响其活性。该提案的长期教育目标是促进和培训下一代科学家在学术界、工业和临床环境中工作，开发创新的生物材料，以提高人类的生活质量。该计划的主要目标是：1)向K-12学生介绍生物材料科学(开发实践科学课程，实施实践研究经验，并鼓励STEM校园实地考察)，2)提高本科生对未被充分代表的学生(西班牙裔、非裔美国人和女性)的研究接触和经验，以及3)扩大东北大学的合作模式，将研究生和学术实验室经验包括在内。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。