Nanomedicine development center for mechanobiology

机械生物学纳米医学发展中心

• 批准号: 8791721
• 负责人: Michael Loran Dustin
• 金额: $ 17.42万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791721
• 关键词: Address; Adoptive Immunotherapy; Antigenic Specificity; Behavior Control; Biology; CD34 gene; CD4 Positive T Lymphocytes; Cell Culture System; Cell Differentiation process; Cell Transplants; Cells; Chemicals; Clinic; Clinical; Computational Biology; Cytoprotection; Dendritic Cells; Development; Diffusion; Engineering; Frequencies; Gene Expression; Generations; Goals; Hematopoietic; Human; Immune; Immune system; Immunologic Deficiency Syndromes; Immunology; Immunotherapy; Lead; Life; Long-Term Effects; Malignant Neoplasms; Mechanics; Memory; Modeling; Morbidity - disease rate; Mus; Nature; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physics; Population; Positioning Attribute; Pre-Clinical Model; Preventive; Property; Quality of life; Regulatory T-Lymphocyte; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Source; Surface; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Vaccines; abstracting; base; cancer immunotherapy; cell type; chemotherapy; graft vs host disease; immunopathology; improved; in vivo; inhibitor/antagonist; leukemia; lymph nodes; mortality; mouse model; multidisciplinary; nano; nanomedicine; nanoparticle; novel; pathogen; pre-clinical; prevent; reconstitution; research clinical testing; scale up; self-renewal; small molecule; tumor

B. Abstract and Specific Aims The goals of our center are to 1) elucidate the mechanical biology of T cells 2) use this understanding of T cell mechanical biology to develop novel T cell culture systems and engineered T cells for improved therapeutics. Adoptive immunotherapy overcomes many obstacles that limit vaccine strategies, by adoptively transferring T cells with controlled antigenic specificity. In addition, ex vivo culture of T cells allows for the generation of large numbers of T cells, which is of utmost importance in the face of T cell deficiencies in cancer. A major current challenge in adoptive immunotherapy is to control self-renewal potential of T cell, often referred to in immunology as "memory", as it allows the immune system to maintain a higher frequency of T cells specific for pathogens encountered earlier. Another issue is self-renewal capacity in effector populations such as Th17 CD4 cells that are high effective in adoptive immunotherapy models. Hence, by engineering this property into T cells used in adoptive immunotherapy, both the immediate and long-term effects of therapy could be improved. Our NDC hypothesized that the IS integrates chemical and mechanical signals to determine the course of T cell differentiation. A major goal of our center is thus to improve immunotherapy by controlling the phenotype and function of ex vivo expanded T cells and in scalable numbers. We will focus on immunotherapy of cancers including both leukemias and solid tumors. Besides using adoptive immunotherapy to selectively and directly attack the tumor or tumor stroma, immunotherapy can be used to protect the patient from immunopathology resulting from treatment efforts. During treatment of leukemia by hematopoietic cell transplant (HCT), which aims at reconstituting the recipient with hematopoietic and immune cells post chemotherapy, donor T cells can cause graft-versus-host-disease (GVHD) - a significant source of morbidity and mortality post-HCT. Current approaches to prevent GVHD, which rely on the use of conventional drugs, and often lead to immunodeficiency, are not satisfactory and new GVHD preventive approaches are clearly needed. Therefore, within our goal of improving patient survival and quality of life, we also plan to make use of regulatory T cells (Tregs) to protect patients from the GVHD toxic effect by modulating Treg function and potency.

B. 摘要和具体目标 我们中心的目标是 1) 阐明 T 细胞的机械生物学 2) 利用对 T 细胞的理解 机械生物学开发新型 T 细胞培养系统和工程化 T 细胞以改进治疗方法。 过继免疫疗法通过过继转移 T 克服了限制疫苗策略的许多障碍 具有受控抗原特异性的细胞。此外，T 细胞的离体培养可以产生大量 T 细胞的数量，这对于癌症中 T 细胞的缺乏至关重要。主要电流 过继性免疫疗法的挑战是控制 T 细胞的自我更新潜力，通常在 免疫学被称为“记忆”，因为它可以让免疫系统保持较高频率的特异性T细胞 较早遇到的病原体。另一个问题是效应细胞群体（例如 Th17）的自我更新能力 CD4 细胞在过继性免疫治疗模型中非常有效。因此，通过将该属性设计成 T 细胞用于过继性免疫疗法，治疗的即时和长期效果都可以 改善了。我们的 NDC 假设 IS 集成了化学和机械信号来确定 T细胞分化过程。因此，我们中心的一个主要目标是通过控制 离体扩增的 T 细胞的表型和功能，并且数量可扩展。我们将重点关注免疫治疗 包括白血病和实体瘤在内的癌症。除了使用过继免疫疗法来选择性地 并直接攻击肿瘤或肿瘤基质，可以使用免疫疗法来保护患者免受 治疗努力产生的免疫病理学。造血细胞治疗白血病过程中 移植（HCT），旨在用造血细胞和免疫细胞重建受者 化疗时，供体 T 细胞可引起移植物抗宿主病 (GVHD)——这是发病率的一个重要来源 和 HCT 后的死亡率。目前预防 GVHD 的方法依赖于使用常规药物， 并经常导致免疫缺陷，但效果并不令人满意，新的 GVHD 预防方法显然是 需要。因此，在提高患者生存率和生活质量的目标范围内，我们还计划利用 调节性 T 细胞 (Treg) 通过调节 Treg 功能和保护患者免受 GVHD 毒性作用 效力。

项目成果

Improving T Cell Expansion with a Soft Touch.

• DOI: 10.1021/acs.nanolett.6b04071
• 发表时间: 2017-02-08
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Lambert LH;Goebrecht GK;De Leo SE;O'Connor RS;Nunez-Cruz S;Li TD;Yuan J;Milone MC;Kam LC
• 通讯作者: Kam LC

Dynamic regulation of the structure and functions of integrin adhesions.

• DOI: 10.1016/j.devcel.2013.02.012
• 发表时间: 2013-03-11
• 期刊: DEVELOPMENTAL CELL
• 影响因子: 11.8
• 作者: Wolfenson, Haguy;Lavelin, Irena;Geiger, Benjamin
• 通讯作者: Geiger, Benjamin

Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.

• DOI: 10.1056/nejmoa1103849
• 发表时间: 2011-08-25
• 期刊: The New England journal of medicine
• 作者: Porter DL;Levine BL;Kalos M;Bagg A;June CH
• 通讯作者: June CH

Dynamic microRNA gene transcription and processing during T cell development.

• DOI: 10.4049/jimmunol.1103175
• 发表时间: 2012-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kirigin FF;Lindstedt K;Sellars M;Ciofani M;Low SL;Jones L;Bell F;Pauli F;Bonneau R;Myers RM;Littman DR;Chong MM
• 通讯作者: Chong MM

Nanoengineering of Immune Cell Function.

免疫细胞功能的纳米工程。

• DOI: 10.1557/proc-1209-yy03-01
• 发表时间: 2009
• 期刊: Materials Research Society symposia proceedings. Materials Research Society
• 作者: Shen,Keyue;Milone,MichaelC;Dustin,MichaelL;Kam,LanceC
• 通讯作者: Kam,LanceC