CAREER: Deciphering the nanoparticle-lymphatic vessel interface for modulating immunity

职业：破译纳米颗粒-淋巴管界面以调节免疫力

• 批准号: 2047017
• 负责人: Katharina Maisel
• 金额: $ 63.63万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047017&HistoricalAwards=false
• 关键词: CAREER; Deciphering; nanoparticle; lymphatic; vessel

Non-Technical Abstract:The PI’s lab’s long-term research goal is to design nanoparticles to transport drugs across and study biological barrier-nanoparticle interfaces to improve therapeutic outcomes, particularly those modulating the immune response. This CAREER proposal will be the first stepping-stone toward achieving the long-term research goal. Therapeutic treatments targeting the immune system range from classic vaccines to allergen immunotherapy to cancer immunotherapies. Targeting lymph nodes directly has been shown to significantly enhance efficacy of immunotherapies, both for vaccination and immunotherapies. This is often done via direct injection into the lymph nodes, but using the natural transport function of lymphatic vessels, by employing small nanoparticles, is a promising, less invasive alternative. In this proposal, the PI will address the gaps in knowledge on how material properties like shape and surface chemistry as well as fluid flow within tissues affect nanoparticle transport by lymphatic vessels. The results from the proposed studies will provide a set of design criteria for developing vaccines and immunotherapies that non-invasively target lymph nodes, which will also enhance acceptability and translatability of such therapeutics. Furthermore, lymphatic transport targeting nanoparticle therapeutics could significantly enhance efficacy of immunotherapies and vaccines, by e.g. providing longer protection against pathogens or enhancing response to cancer immunotherapy, all while reducing side effects and required doses. The proposed research will be integrated into a transformative education and outreach program to teach critical thinking and interpretation of data and promote inclusion and retention of underrepresented groups, particularly women, in engineering. Toward the first goal, the PI will design in-class laboratory exercises that are supplemented with real-world data from the research objectives to illustrate complexities of biological systems. Diversity in engineering is still far below that of the general population and research has shown that diversity in teams and researchers increases creativity, achievement, and outside-the-box thinking. The PI has developed a 3-pronged approach that builds upon two main principles identified to aid in retention and recruitment of diverse groups in STEM: mentorship and inclusive leadership. For this CAREER award, the PI will build generational and peer mentorship programs, increase dissemination of mentorship training programs, design diversity education modules to educate the next and current generation of scientists on promoting inclusive environments, and finally, build early-stage interventions by partnering with rural elementary schools to recruit women and underrepresented groups into STEM careers. The long-term outcome is to strengthen the participation of diverse groups in STEM through exposure and educational opportunities and tools to maintain and encourage diversity in teams and research at all levels.Technical Abstract:The PI’s lab’s long-term research goal is to design nanoparticles to study biological barrier-nanoparticle interfaces to improve therapeutic outcomes. This CAREER award will be the first stepping-stone to achieve the long-term research goal by investigating the nanoparticle interface with lymphatic vessels (‘lymphatics’). Lymphatics have crucial transport roles, shuttling antigens and particulates from peripheral tissues to the draining lymph nodes (dLNs), where the adaptive immune response is shaped. Reaching the dLNs has been shown to particularly amplify the effectiveness of immunotherapies and vaccines and can be achieved by targeting lymphatics using small particulates between 10 – 200 nm. But many questions remain unanswered: how do material properties, like shape and surface characteristics, affect transendothelial transport of nanoparticles and the mechanisms involved in this transport? In this CAREER award, the PI will 1) investigate the effects of nanoparticle properties such as shape and surface chemistry on their transport by lymphatics, 2) determine how interstitial flow modulates transport of these different nanoparticle formulations, 3) assess nanoparticle protein corona formation and stability in lymph fluid, and 4) elucidate the cellular mechanisms used by lymphatics to transport nanoparticles with different material properties. The PI’s long-term educational goal is to develop experiential learning experiences and build educational tools to recruit and retain underrepresented groups in engineering. The first educational goal will be to design in-class laboratory exercises that are supplemented with real-world data from the research objectives to illustrate complexities of biological systems. Research has shown that diversity in teams and researchers increases creativity, achievement, and outside-the-box thinking. The PI has developed a 3-pronged approach that builds upon two main principles identified to aid in retention and recruitment of diverse groups in STEM: mentorship and inclusive leadership. The PI will 1) build generational and peer mentorship programs, 2) increase dissemination of mentorship training programs, 3) design diversity education modules to educate the next and current generation of scientists on promoting inclusive environments, and 4) build early-stage interventions by partnering with rural elementary schools to recruit women and underrepresented groups into STEM careers. The proposed research will lead to crucial advances in fundamental understanding of how nanoparticle properties 1) modulate transport by lymphatics, particularly in the context of interstitial fluid flow, and 2) affect cellular mechanisms used by lymphatics to transport nanoparticles across the vessel wall. This fundamental understanding will provide rational material-based design criteria for nanoparticle platforms that can be used as probes to study lymphatic transport physiology and to deliver immunotherapies and vaccines.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.

摘要：PI实验室的长期研究目标是设计纳米颗粒来运输药物，并研究生物屏障-纳米颗粒界面，以改善治疗效果，特别是那些调节免疫反应的纳米颗粒。这份职业计划书将是实现长期研究目标的第一块踏脚石。针对免疫系统的治疗方法包括从经典疫苗到过敏原免疫疗法再到癌症免疫疗法。直接靶向淋巴结已被证明可以显著提高免疫疗法的疗效，无论是疫苗接种还是免疫疗法。这通常是通过直接注射到淋巴结来完成的，但利用淋巴管的自然运输功能，通过使用小纳米颗粒，是一种有希望的，侵入性较小的替代方法。在这个提案中，PI将解决诸如形状和表面化学等材料特性以及组织内流体流动如何影响纳米颗粒通过淋巴管运输的知识空白。拟议研究的结果将为开发非侵入性靶向淋巴结的疫苗和免疫疗法提供一套设计标准，这也将提高此类疗法的可接受性和可翻译性。此外，靶向纳米颗粒疗法的淋巴转运可以显著提高免疫疗法和疫苗的功效，例如，提供更长的对病原体的保护或增强对癌症免疫疗法的反应，同时减少副作用和所需剂量。拟议的研究将被纳入一项变革性的教育和推广计划，以教授批判性思维和数据解释，并促进工程领域代表性不足的群体（尤其是女性）的包容和保留。为了实现第一个目标，PI将设计课堂上的实验室练习，并辅以来自研究目标的真实世界数据，以说明生物系统的复杂性。工程领域的多样性仍然远远低于一般人群，研究表明，团队和研究人员的多样性可以提高创造力、成就和跳出框框的思维。PI制定了一个三管齐下的方法，该方法建立在两个主要原则的基础上，以帮助保留和招募STEM领域的不同群体：指导和包容性领导。对于这个职业奖，PI将建立代际和同伴指导计划，增加指导培训计划的传播，设计多元化教育模块，教育下一代和当代科学家促进包容性环境，最后，通过与农村小学合作，建立早期干预措施，招募妇女和代表性不足的群体进入STEM职业。长期成果是通过接触和教育机会和工具加强不同群体对STEM的参与，以保持和鼓励各级团队和研究的多样性。技术摘要：PI实验室的长期研究目标是设计纳米颗粒来研究生物屏障-纳米颗粒界面，以改善治疗效果。通过研究纳米颗粒与淋巴管（淋巴管）的界面，该CAREER奖将成为实现长期研究目标的第一块踏脚石。淋巴具有重要的运输作用，将抗原和微粒从外周组织运送到引流淋巴结（dln），在那里形成适应性免疫反应。研究表明，到达dln可特别增强免疫疗法和疫苗的有效性，并且可以通过使用10 - 200纳米之间的小颗粒靶向淋巴来实现。但许多问题仍未得到解答：材料特性，如形状和表面特性，如何影响纳米颗粒的跨内皮运输以及这种运输涉及的机制？在这个CAREER奖中，PI将1)研究纳米颗粒特性（如形状和表面化学）对其通过淋巴管运输的影响，2)确定间隙流动如何调节这些不同纳米颗粒配方的运输，3)评估纳米颗粒蛋白冠的形成和淋巴液中的稳定性，4)阐明淋巴管运输不同材料特性纳米颗粒的细胞机制。PI的长期教育目标是开发体验式学习体验，并建立教育工具，以招募和留住工程领域代表性不足的群体。第一个教育目标将是设计课堂上的实验练习，并辅以来自研究目标的真实世界数据，以说明生物系统的复杂性。研究表明，团队和研究人员的多样性可以提高创造力、成就和创新思维。PI制定了一个三管齐下的方法，该方法建立在两个主要原则的基础上，以帮助保留和招募STEM领域的不同群体：指导和包容性领导。该项目将1)建立代际和同伴指导项目，2)增加指导培训项目的传播，3)设计多元化教育模块，教育下一代和当代科学家促进包容性环境，4)通过与农村小学合作，建立早期干预措施，招募女性和代表性不足的群体进入STEM职业。这项拟议的研究将导致对纳米颗粒特性如何在基本理解方面取得关键进展：1)调节淋巴管运输，特别是在间质液流动的背景下；2)影响淋巴管运输纳米颗粒穿过血管壁的细胞机制。这种基本的理解将为纳米粒子平台提供合理的基于材料的设计标准，纳米粒子平台可以用作研究淋巴运输生理学和提供免疫疗法和疫苗的探针。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Overcoming transport barrier to immunotherapies

克服免疫疗法的运输障碍

• DOI: 10.1007/s13346-021-01080-8
• 发表时间: 2021
• 期刊: Drug Delivery and Translational Research
• 影响因子: 5.4
• 作者: Maisel, Katharina

Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells

• DOI: 10.1021/acs.molpharmaceut.3c00720
• 发表时间: 2023-10-18
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: McCright，Jacob;Yarmovsky，Jenny;Maisel，Katharina
• 通讯作者: Maisel，Katharina

Equitable hiring strategies towards a diversified faculty

面向多元化教师的公平招聘策略

• DOI: 10.1038/s41551-023-01076-4
• 发表时间: 2023
• 期刊: Nature Biomedical Engineering
• 影响因子: 28.1
• 作者: Cosgriff-Hernandez, Elizabeth M.;Aguado, Brian A.;Akpa, Belinda;Fleming, Gabriella Coloyan;Moore, Erika;Porras, Ana Maria;Boyle, Patrick M.;Chan, Deva D.;Chesler, Naomi;Christman, Karen L.
• 通讯作者: Christman, Karen L.

Discussion-Based DEI Education to Help Create Inclusive and Open BME Research Lab Environments

基于讨论的 DEI 教育有助于创建包容性和开放的 BME 研究实验室环境

• DOI: 10.1007/s43683-022-00074-3
• 发表时间: 2022
• 期刊: Biomedical Engineering Education
• 作者: Naiknavare, Ritika;Maisel, Katharina
• 通讯作者: Maisel, Katharina

Your peers are your pillars

你的同伴是你的支柱

• DOI: 10.1126/science.acx9414
• 发表时间: 2021
• 期刊: Science
• 影响因子: 56.9
• 作者: Maisel, Katharina