Understanding the Molecular Mechanisms of Early Postnatal Development of Pig Islets

了解猪胰岛产后早期发育的分子机制

• 批准号: RGPIN-2017-05816
• 负责人: Rayat, Gina
• 金额: $ 1.82万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=681273
• 关键词: Understanding; Molecular; Mechanisms; Early; Postnatal

Very few studies in rodents have investigated the development of islets after birth and none so far has examined the development of pig islets during postnatal period in particular, the role of cell adhesion molecules, cadherins in this process. Thus, novel findings from my NSERC program will provide a better understanding on the molecules involve in the formation and maintenance of islet architecture as well as normal function of islets after birth. In addition, the vascular endothelial components of pig islets are poorly understood. It has been known for some time that islets from adult pigs are difficult to isolate and maintain in culture due to their fragile nature compared to islets from newborn pigs, which make the latter an attractive source of islets for transplantation. In addition, it has been known for some time that newborn pig islets have the capacity to grow into mature islets. However, the processes involved in the maturation of newborn pig islets remain to be elucidated. I suspect that cadherins may explain in part the differences we observed between newborn and adult pig islets. Since I started working on newborn pig islets the focus of majority of studies in the field has been on developing strategies on how to prevent their rejection. These strategies involved the genetic engineering of pig islet donors among others and their ability to survive and function in large animal models including non-human primates has been proven to be successful. However, these recipients were heavily immunosuppressed and these regimens are very toxic and are not applicable to human patients. As more and more genetically engineered pigs being created worldwide as source of islets for transplantation, the basic biology of pig islets has not been intensively studied. Thus, our understanding of the tissue we hope to use as a possible solution to the shortage of human islets for transplantation has been limited. I believe that understanding the basic biology of pig islets is fundamental in the successful translation of pig islet transplantation to the clinic. I also believe that the more we know about the tissue we are using for transplantation the more we will be able to successfully transplant the tissue without using immunosuppressive drugs. These drugs are harmful to the tissue itself as well as they pose major risk of infection and development of cancer in islet transplant recipients.

很少有啮齿类动物研究出生后胰岛的发育，到目前为止还没有研究猪胰岛在出生后的发育，特别是细胞粘附分子，钙粘蛋白在这个过程中的作用。因此，我的NSERC项目的新发现将更好地了解参与胰岛结构形成和维持以及出生后胰岛正常功能的分子。此外，猪胰岛的血管内皮成分知之甚少。一段时间以来，已知来自成年猪的胰岛由于其与来自新生猪的胰岛相比的脆弱性质而难以分离和维持在培养物中，这使得后者成为用于移植的有吸引力的胰岛来源。此外，一段时间以来，人们已经知道新生猪胰岛具有生长成成熟胰岛的能力。然而，新生猪胰岛成熟的过程仍有待阐明。我怀疑钙粘蛋白可以部分解释我们在新生猪和成年猪胰岛之间观察到的差异。自从我开始研究新生猪胰岛以来，该领域大多数研究的重点都是如何防止它们的排斥反应。这些策略涉及猪胰岛供体的基因工程，并且它们在包括非人灵长类动物在内的大型动物模型中存活和发挥作用的能力已被证明是成功的。然而，这些受体严重免疫抑制，这些方案毒性很大，不适用于人类患者。随着世界范围内越来越多的基因工程猪作为胰岛移植的来源，猪胰岛的基础生物学尚未得到深入研究。因此，我们对我们希望用作解决人类胰岛移植短缺的可能解决方案的组织的了解有限。我相信了解猪胰岛的基本生物学是将猪胰岛移植成功应用于临床的基础。我还相信，我们对用于移植的组织了解得越多，我们就越能够成功地移植组织而不使用免疫抑制药物。这些药物对组织本身有害，并且它们在胰岛移植受者中构成感染和癌症发展的主要风险。