不列颠哥伦比亚省科学家Emrah Altindis获得2美元.NIH拨款500万
Assistant Professor of Biology Emrah Altindis has been awarded a five-year, $2.5-million grant from the National Institutes of Health to advance his research on viral insulins into the understanding of mechanisms related to IGF-1 receptor protein inhibition and its potential applications in cancer treatment.
Altindis说 the grant will enable him and the researchers in his lab to learn more about how to use 具体的 viral insulins that mimic human insulin so as to inhibit IGF-1 receptor action, 在一系列疾病中哪一种会增加, 包括人类癌症.
“I am very excited about our viral insulin project and grateful to the National Institutes of Health for this essential support as we move forward,阿尔廷迪斯说. “We have made some important discoveries related to unique functions of these viral insulins that are pointing us in the right direction to develop novel therapeutics to inhibit an important receptor and, 最终, 改善人类健康.”
The Altindis lab has discovered that six viruses mimic human insulin and insulin-like growth factor-1 (IGF-1) and have special peptides, 他的团队将其命名为“VILPs”——病毒胰岛素/ igf样肽.
Their research is focused on learning more about how these viral insulins work. 重要的是, the lab’s experiments have discovered that only two of these VILPs can uniquely block an important receptor called insulin-like growth factor receptor (IGF1-R), 哪一种在包括乳腺癌在内的不同疾病中过度活跃, 卵巢, 前列腺癌, Altindis说.
Scientists have been searching for ways to inhibit this receptor for the past three decades, 但还没有取得成功. 获得NIH奖, from the agency’s National Institute of Diabetes and Digestive and Kidney Diseases, Altindis and his team are trying to more precisely determine how VILPs can block the IGF1 receptor.
Learning that could lead to affordable and 具体的 treatments that inhibit the receptor for a range of diseases.
Viruses are known to mimic the host’s immune system proteins to manipulate the host during infection. However, the Altindis lab’s discovery identified another mimicry mechanism. 在这些病毒胰岛素的情况下, 病毒模仿两种重要的人类荷尔蒙, 胰岛素和IGF-1, 并通过胰岛素受体和IGF-1受体起作用. 胰岛素调节细胞代谢, and impairment of insulin receptor signaling causes insulin resistance and type 2 diabetes. 另一方面, IGF-1受体刺激增殖和细胞生长, and any impairment is related to growth disorders and uncontrolled proliferation.
Emrah Altindis(摄影:Lee Pellegrini)
“在过去的六年里, we have shown that these VILPs can bind and activate the human insulin receptor and IGF-1 receptor,阿尔廷迪斯说. “与他人, two of the VILPs we identified have a unique function: binding and 具体的ally inhibiting the IGF-1 receptor without affecting insulin receptor function.”
胰岛素受体和IGF-1受体在结构上非常相似. 因此, the challenge for Altindis and his fellow scientists has been trying to stop the cell proliferation triggered by IGF-1 by inhibiting IGF-1 receptors without affecting insulin receptor signaling.
使用实验室模型, the Altindis lab will investigate how VILPs interact with IGF1R using advanced techniques, 包括CryoEM成像和TurboID标记. 除了, they will use phosphoproteomics to understand the unique signaling events stimulated by the VILPs. 另外, experiments will explore the effects of VILPs on IGF-1 signaling and growth in different tissues. 最后, Altindis说 the team should be able to determine the effects of these VILPs on cancer cell proliferation in the lab focusing on breast cancer and in related mouse models.
据我们所知, VILPs represent the first potent and 具体的 peptide inhibitors of the IGF-1 receptor,阿尔廷迪斯说. “在这个项目中，我们的重点是了解它们的作用机制. Addressing this question will guide us in developing even more effective inhibitors of the receptor.”
阿尔廷迪斯说，迫切需要开发一种有效的药物, 具体的, and affordable IGF-1 receptor inhibitors to treat IGF1R-related cancers and other diseases like Graves’ disease. 在理想的情况下, these inhibitors could be used in combination with other therapies to treat cancer in humans. He believes the project has the potential to impact both the basic understanding of the IGF-1 receptor action as well as lead to the development of novel treatment approaches for breast cancer.
“The challenge lies in translating these findings into practical treatments for diseases,阿尔廷迪斯说. “This study lays the foundation for future research and clinical developments in the field of IGF-1-related disorders. We hope to generate significant new insights into our understanding of IGF-1 signaling and inhibition that will eventually lead to the design of inhibitors that can be used to treat human disease.”
Altindis说 the NIH grant is the result of collaborative work with peers, 包括印第安纳大学的理查德·迪马奇, 有机化学和生物化学电子游戏正规平台所的Jiri Jiracek说, 在布拉格, Nicholas Kirk of Walter and Eliza Hall Institute of Medical Research in Australia, 以及马萨诸塞大学陈医学院的杰森·金. He also acknowledged Joslin Diabetes Center and Harvard Medical School Professor C. 罗纳德·卡恩, 他的博士后导师, for introducing him to the insulin/IGF field in 2014 and to fellow researcher François Moreau.
“I also want to express my gratitude to all members of my lab who have been very supportive and productive in the last five years at BC, 尤其是我们的前博士后玛蒂娜·克鲁迪诺娃, 谁在这个项目上做了大量的工作,阿尔廷迪斯说. “非常感谢我们在BC的核心设施, 管理员, and colleagues in the 生物系 and the University for their extensive support of our research.”