Regulation of TGF-beta signalling by focal adhesion proteins

我们的长期研究目标是了解生长因子受体和整合素之间的交叉调节，这是发育和细胞分化等生理过程的基础。我们的方法包括利用转基因小鼠改变整合素功能，这允许进行体内研究，并辅之以对培养细胞的研究，以了解相关的分子机制。我们还通过在整合素中引入位点特异性突变，或通过删除/修改将整合素反应与生长因子途径联系起来的下游信号分子来修改信号特性。一类这样的下游分子是Kindlins。在中短期内，我们的目标是阐明Kindlins在这些过程中的作用。本应用的目的是阐明kindlin-2在转化生长因子-？(转化生长因子？)信号通路中的作用。我们假设kindlin-2通过调节受体的运输和稳定性来调节转化生长因子-β信号转导。我们处于开展这项拟议研究的绝佳位置，因为我们已经开发出了我们实验室独有的强大的细胞模型和试剂。这些研究将提供对迄今为止知之甚少的通路的作用的关键洞察，涉及整合素、Kindlins和转化生长因子-B。此外，这项研究还将加深我们对不同来源细胞中基本信号转导机制的理解，目前对这些机制了解很少，但从哺乳动物到无脊椎动物都有。

Our long-term research goal is to understand the cross-modulation of growth factor receptors and integrins, fundamental to physiological processes, such as development and cell differentiation. Our approaches include altering integrin functions using genetically modified mice, which allow in vivo studies, complemented with studies on cultured cells to understand relevant molecular mechanisms. We also modify signaling properties by introducing site-specific mutations in integrins, or by deleting/modifying downstream signaling molecules that link integrin responses with growth factor pathways. A class of such downstream molecules are the kindlins. Over the short-to-medium term, we aim at elucidating the roles of kindlins in these processes. The objective of this application is to elucidate the role of kindlin-2 on transforming growth factor-ß (TGF-ß) signaling pathways. We hypothesize that kindlin-2 modulates TGF-ß signaling by regulating receptor trafficking and stability. We are in an excellent position to undertake the proposed research, as we have developed powerful cell models and reagents unique to our laboratory. These studies will provide critical insight into the role of pathway poorly understood to-date, involving integrins, kindlins and TGF-ß. Moreover, this research will also enhance our understanding of basic signal transduction mechanisms in cells of various origins, currently very poorly understood, but widespread from mammals to invertebrates.