权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Supramolecular hydrogels for localized delivery of immunomodulatory enzymes

用于局部递送免疫调节酶的超分子水凝胶

基本信息

批准号：
9750094
负责人：
Gregory Hudalla
金额：
$ 18.41万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750094
关键词：
Address Adenosine Adenosine Triphosphate Anti-inflammatory Apyrase Biocompatible Materials Biological Cell membrane Cells Charge Chimeric Proteins Chronic Clinical Diffuse Diffusion Disease Elements Enzymes Equilibrium Fever Financial Hardship Functional disorder Future Gel Grant Half-Life Homeostasis Hydration status Hydrogels Immune Immune response Immune system Immunocompromised Host Immunologics Immunosuppressive Agents Immunotherapeutic agent In Vitro Individual Inflammation Inflammatory Innate Immune System Lead Lipopolysaccharides Mediating Membrane Modality Modeling Molecular Mus Opportunistic Infections Pain management Pathology Patients Pattern Peptides Pharmaceutical Preparations Play Polymers Pre-Clinical Model Purinergic P2 Receptors Research Resolution Role Route Self-Direction Signal Transduction Site Subcutaneous Injections Therapeutic Uses Time Tissues Wound Healing adaptive immune response base beta pleated sheet cell injury clinical efficacy cost cytokine effective therapy extracellular immune system function immunoregulation in vitro Model in vivo in vivo Model innovation macrophage minimally invasive monocyte nanofiber pathogen preclinical safety programs receptor residence response small molecule standard of care subcutaneous success therapeutic enzyme

项目摘要

Project summary. The innate immune system plays an essential role in protecting host tissue function by eradicating pathogens and other foreign elements, promoting proper wound healing, and maintaining tissue homeostasis. However, dysregulated innate immune system activation resulting from aberrant self-directed immune responses can lead to states of chronic local inflammation that induce tissue damage or dysfunction. Chronic inflammatory diseases are often incurable, and therefore the current standard of care involves managing pain or fever via drugs that inhibit pro-inflammatory cytokines or their receptors. Although effective, these treatment modalities can suppress immune system function and render patients susceptible to opportunistic infections. In contrast, natural resolution of inflammation is mediated in part by enzymes anchored to the cell membrane that convert immunostimulatory signals to an inactive, or in some cases immunosuppressive, form. For example, extracellular ATP (eATP) released by one’s own damaged or dying cells acts as a ‘danger signal’ that activates inflammation, and eATP immunostimulatory activity is locally regulated by membrane-anchored enzymes that dephosphorylate ATP to adenosine (Ado), an immunosuppressive signal. Inspired by these observations, an ATP dephosphorylating enzyme, apyrase, is currently investigated as an immunotherapeutic biologic, and has demonstrated efficacy for suppressing inflammation in pre-clinical models. However, clinical efficacy of soluble apyrase delivered via parenteral routes is likely to be hindered by the short effective half-life typical of biologic drugs. To address this limitation, the proposed research program will develop biomaterials with integrated ATP dephosphorylating enzymes as immunotherapeutics that can be locally delivered to specific tissue sites to suppress aberrant inflammation. Toward this end, the proposed research program will create hydrated polymeric gels (i.e. “hydrogels”) of self- assembled peptide nanofibers with integrated enzymes that dephosphorylate ATP to Ado. Specifically, we will adapt our established platform, Co-Assembly Tags based on CHarge complementarity (“CATCH”), to create hydrogels harboring Adenosine Synthase A (AdsA), an enzyme that dephosphorylates ATP to Ado. Through this grant, we will (i) optimize CATCH-AdsA hydrogel enzymatic activity through material redesign, (ii) assess CATCH-AdsA hydrogel efficacy for immunomodulation using in vitro and in vivo models, and (iii) establish a pre-clinical safety profile for these biomaterials by assessing host innate and adaptive immune responses to CATCH hydrogels and their individual components. Success of the proposed research will lead to new biomaterials that can locally suppress inflammation via presentation of an immunomodulatory enzyme, which will provide the basis for future efforts to develop new immunotherapeutics to resolve chronic inflammation. More generally, a biomaterial platform with interchangeable integrated enzyme components is likely to enable new opportunities to harness natural enzymatic mechanisms to treat various immune-related pathologies.

项目总结。先天免疫系统在保护宿主组织功能方面起着至关重要的作用清除病原体和其他外来因素，促进伤口愈合，维护组织动态平衡。然而，异常自我定向导致的先天性免疫系统激活失调免疫反应可导致慢性局部炎症状态，从而导致组织损伤或功能障碍。慢性炎症性疾病通常是无法治愈的，因此目前的护理标准包括通过抑制促炎细胞因子或其受体的药物来控制疼痛或发烧。虽然很有效，这些治疗方式会抑制免疫系统功能，使患者容易患上机会性感染。相反，炎症的自然消退部分是由酶介导的。锚定在细胞膜上，将免疫刺激信号转化为非活性信号，或者在某些情况下免疫抑制，形式。例如，细胞外的三磷酸腺苷(EATP)由自己受损或死亡所释放细胞充当激活炎症的“危险信号”，eATP免疫刺激活性是局部的由膜锚定的酶调节，使ATP脱磷为腺苷(ADO)，以及免疫抑制信号。受到这些观察的启发，一种名为apyrase的三磷酸腺苷脱磷酸酶目前作为一种免疫治疗生物被研究，并已证明对抑制临床前模型中的炎症。然而，肠外注射可溶性apyrase的临床疗效生物药物的典型有效半衰期很短，这很可能阻碍药物的应用。为了解决这一限制，拟议的研究计划将开发具有集成的ATP脱磷酸酶的生物材料，如可局部输送到特定组织部位以抑制异常炎症的免疫疗法。为此，拟议的研究计划将创造水合聚合物凝胶(即“水凝胶”)的自我组装了带有集成酶的多肽纳米纤维，这些酶可以将ATP脱磷为腺苷。具体来说，我们将调整我们已建立的平台，基于电荷互补的联合组装标签(CATCH)，以创建含有腺苷合成酶A(ADSA)的水凝胶，ADSA是一种将ATP脱磷为腺苷的酶。穿过这笔赠款，我们将(I)通过材料重新设计优化Catch-ADSA水凝胶酶活性，(Ii)评估利用体外和体内模型研究Catch-ADSA水凝胶的免疫调节作用，以及(Iii)建立通过评估宿主先天和获得性免疫反应来评估这些生物材料的临床前安全性捕捉水凝胶及其个别成分。拟议研究的成功将带来新的生物材料可以通过呈递免疫调节酶来局部抑制炎症，这种酶将为未来开发新的免疫疗法以解决慢性炎症提供基础。更广泛地说，具有可互换集成酶组分的生物材料平台可能能够利用自然酶机制治疗各种免疫相关疾病的新机会。