Development of platforms for beta cell-specific delivery and ligand discovery

开发β细胞特异性递送和配体发现平台

• 批准号: 10738505
• 负责人: Amit Choudhary
• 金额: $ 94.37万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738505
• 关键词: Adipose tissue; Beta Cell; Binding; Biology; Cadaver; Cell Proliferation; Cell Transplantation; Cells; Cessation of life; Chemicals; Chemistry; Dependence; Development; Disease; Functional disorder; Graft Rejection; Human; Immune system; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Ions; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Libraries; Ligand Binding; Ligands; Link; Liver; Mechlorethamine; Methods; Mitogens; Modality; Muscle; Nature; Oranges; Organism; Patients; Pharmaceutical Preparations; Plasma; Procedures; Prodrugs; Proliferating; Reaction; Reagent; Replacement Therapy; Skeletal Muscle; Sorting; Specificity; System; Techniques; Testing; Therapeutic; Time; Zinc; cell type; chemical reaction; efficacy evaluation; efficacy testing; fluorophore; improved; in vivo; in vivo evaluation; islet; pharmacologic; small molecule; stem cell proliferation; therapeutic development; therapeutic target

Patients suffering from type 1 diabetes must undergo burdensome, often lifelong, exogenous insulin dependence. Up to now, the only available replacement therapy is to transplant islets from cadaveric donors. However, such procedures present hurdles such as the scarcity of available donors and the rejection of transplanted cells by the patient’s own immune system. Also, over time, the transplanted islets tend to die. To circumvent these effects, we and other have identified several therapeutic targets to induce beta cell proliferation. However, the realization of the therapeutic potential of these targets requires targeted release as the therapeutic window of these targets is narrow. We propose to apply chemical biology approaches to develop methods for targeted release of bioactives in beta cells in vivo. 1

患有1型糖尿病的患者必须经历沉重的、通常是终身的外源性胰岛素依赖。到目前为止，唯一可用的替代疗法是从尸体供体移植胰岛。然而，这些程序存在障碍，例如可用供体的稀缺以及患者自身免疫系统对移植细胞的排斥。此外，随着时间的推移，移植的胰岛往往会死亡。为了避免这些影响，我们和其他人已经确定了几个治疗靶点，以诱导β细胞增殖。然而，这些靶标的治疗潜力的实现需要靶向释放，因为这些靶标的治疗窗很窄。我们建议应用化学生物学方法来开发在体内β细胞中靶向释放生物活性物质的方法。 1