Combining Bacterial Glycosylation Tools and Nanotechnology to Optimize Siglec Ligands for the Treatment of Allergy and Anaphylaxis
结合细菌糖基化工具和纳米技术来优化 Siglec 配体,用于治疗过敏和过敏反应
基本信息
- 批准号:10315663
- 负责人:
- 金额:$ 4.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
Allergies are the 6th most common cause of chronic illness in the US, but effective treatment options
remain limited. Recently discovered, cell-specific, inhibitory immune receptors, such as sialic acid-binding
immunoglobulin-type lectin (Siglec) receptors, are promising therapeutic targets to suppress these unwanted
immune responses, but have been difficult to target because they specifically bind sialic-acid containing
carbohydrates, or glycans. Using two newly developed tools: a bacterial glycan-building platform for
constructing modifiable Siglec receptor glycan ligands and a glycan-displaying nanogel capable of varying
glycan density, we aim to generate optimized Siglec receptor ligands towards the development of therapeutic
candidates for the treatment of allergy and prevention of anaphylaxis. We will use Siglec 3 (CD33) as a model
to validate this approach since it is expressed on both mast cells and basophils, two cell types implicated in
allergy and anaphylaxis. In the first aim, we will generate a library of chemically modified glycan variants that
are candidate Siglec receptor ligands to assess for high affinity interactions with ELISA. We will then load high
affinity glycan ligands on nanogels at varying densities, apply to sensitized primary human skin-derived mast
cells, and assess metrics of mast cell activity including release of granule components, surface markers, and
cytokine release. In the second aim, we will supplement the field with a new tool for the characterization of
Siglec receptors. Genomic incorporation of glycosylation machinery in engineered Escherichia coli will yield a
stable strain for generating modifiable sialoglycoproteins that are candidate Siglec ligands. Ultimately, using
bacterial glycoengineering, we will develop a customizable platform for generating Siglec receptor ligands that
can be readily ported to other labs and broadly applied for the characterization of other lectins. Once complete,
the proposed aims will not only yield therapeutic candidates capable of high affinity Siglec 3 (CD33) binding,
but also a new approach and tool that can be applied to identify therapeutic candidates for other Siglec
receptors and lectins. This project spans glycobiology, cell biology, nanomaterials, and using allergy models of
disease. As such, it will provide a rich training experience bolstered by research mentors with synergistic
expertise and ample support from Northwestern University, the Center for Synthetic Biology, the Medical
Scientist Training Program, and the Interdisciplinary Biological Sciences Graduate Program. In addition to
providing a robust training experience, this will work will also advance the therapeutic potential of targeting
Siglec receptors for the treatment of allergy and prevention of anaphylaxis, among other relevant diseases.
项目摘要
过敏是美国慢性病的第六大常见原因,但有效的治疗选择
仍然有限。最近发现,细胞特异性,抑制性免疫受体,如唾液酸结合
免疫球蛋白型凝集素(Siglec)受体是有希望的治疗靶点,以抑制这些不需要的免疫球蛋白。
免疫应答,但由于它们特异性结合含有硫酸的
碳水化合物或聚糖。使用两种新开发的工具:细菌聚糖构建平台,
构建可修饰的Siglec受体聚糖配体和聚糖展示纳米凝胶,
我们的目标是产生优化的Siglec受体配体,以开发治疗性的Siglec受体配体。
用于治疗变态反应和预防过敏反应的候选物。我们将使用Siglec 3(CD33)作为模型
为了验证这种方法,因为它在肥大细胞和嗜碱性粒细胞上都表达,两种细胞类型涉及
过敏和过敏反应。在第一个目标中,我们将产生化学修饰的聚糖变体的文库,
是候选Siglec受体配体,以评估与ELISA的高亲和力相互作用。然后我们将加载高
不同密度的纳米凝胶上的亲和聚糖配体,应用于致敏的原代人皮肤源性肥大细胞
细胞,并评估肥大细胞活性的度量,包括颗粒组分、表面标志物和
细胞因子释放在第二个目标中,我们将用一种新的工具来补充该领域,
Siglec受体。在工程大肠杆菌中糖基化机制的基因组整合将产生一种新的糖基化机制。
用于产生作为候选Siglec配体的可修饰的唾液酸糖蛋白的稳定菌株。最终,使用
细菌糖工程,我们将开发一个可定制的平台来产生Siglec受体配体,
可以很容易地移植到其他实验室,并广泛应用于其他凝集素的表征。一旦完成,
所提出的目的不仅将产生能够高亲和力结合Siglec 3(CD 33)的治疗候选物,
也是一种新的方法和工具,可用于识别其他Siglec的治疗候选物,
受体和凝集素。该项目涵盖糖生物学,细胞生物学,纳米材料,并使用过敏模型,
疾病因此,它将提供丰富的培训经验,并由研究导师提供协同作用,
专业知识和来自西北大学,合成生物学中心,医疗
科学家培训计划和跨学科生物科学研究生计划。除了
提供一个强大的培训经验,这将工作也将推进靶向治疗的潜力
Siglec受体用于治疗变态反应和预防过敏反应以及其他相关疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Ariel Thames', 18)}}的其他基金
Combining Bacterial Glycosylation Tools and Nanotechnology to Optimize Siglec Ligands for the Treatment of Allergy and Anaphylaxis
结合细菌糖基化工具和纳米技术来优化 Siglec 配体,用于治疗过敏和过敏反应
- 批准号:
10507766 - 财政年份:2021
- 资助金额:
$ 4.2万 - 项目类别:
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