TGF beta Receptors and Cell Proliferation

描述（由申请人提供）：转化生长因子β (TGF-?)生物学的一个中心悖论是相同的生长因子如何诱导生长刺激（即间充质细胞）和生长抑制（即上皮细胞）等不同的反应？考虑到TGF-？在一些正常和病理情况下，如果我们希望制定具体的干预战略，解决这个问题是至关重要的。为此，我们一直在研究TGF-？刺激细胞类型特异性信号通路作为调节这些表型的手段。与生长抑制（上皮细胞）细胞对TGF-?的反应相反，在协调促纤维化（即间充质）中起关键作用的一个靶点。PI3K。在之前的融资周期中，我们已经证明PI3K代表了smad无关的TGF-？其中一条手臂导致Pak2和c-Abl的激活，而另一条手臂则与Akt和mTOR偶联。由于这一发现导致了一项多中心II期临床试验，测试甲酸伊马替尼与安慰剂治疗特发性肺纤维化的疗效，我们将使用各种生化、生物学和形态学方法在竞争性更新中扩展这些概念。首先，我们将确定TGF-？mTOR的激活刺激基质细胞增殖。我们提出TGF-?模型可以获得更大的疗效和更低的毒性。通过抑制PI3K下游的Pak2/c-Abl和Akt/mTOR分支来驱动组织纤维化。二、鸟嘌呤核苷酸交换因子（GEF）磷酸化及受体关联在指导TGF-？靶标特异性和受体激活将被确定。第三，已经确定了一种候选蛋白，可以调节成纤维细胞特异性TGF-？信号，实验提出，以确定机制，阻止或促进这些途径的激活分别在上皮细胞和间充质细胞。如果这些过程介导细胞类型特异性TGF-？信号将被阐明。

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-? has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that TGF-? stimulates cell type-specific signaling pathways as a means to regulate these phenotypes. One target with a critical role in coordinating the profibrogenic (i.e., mesenchymal), in contrast to the growth inhibitory (i.e., epithelial), cellular response to TGF-? is PI3K. During the previous funding cycle we have shown that PI3K represents a branchpoint in Smad-independent TGF-? signaling such that one arm leads to activation of Pak2 and c-Abl, while the other is coupled to Akt and mTOR. As this former finding has led to a multi-center Phase II clinical trial testing the efficacy of imatinib mesylate vs. placebo in the treatment of idiopathic pulmonary fibrosis, we will extend these concepts in the competing renewal using a variety of biochemical, biological, and morphologic approaches. First, we will determine the mechanism(s) by which TGF-? activation of mTOR stimulates stromal cell proliferation. It is proposed that greater efficacy and lower toxicity can be obtained in models of TGF-? driven tissue fibrosis by inhibiting both Pak2/c-Abl and Akt/mTOR branches downstream of PI3K. Second, the role of guanine nucleotide exchange factor (GEF) phosphorylation and receptor association in directing TGF-? target specificity and receptor activation will be defined. Third, a candidate protein has been identified which regulates fibroblast-specific TGF-? signaling, experiments are proposed to determine the mechanism(s) which prevents or promotes activation of these pathways in epithelial and mesenchymal cells, respectively. Answers to these questions are critical if the processes mediating cell type-specific TGF-? signaling are to be elucidated. Relevance to public health (lay language): TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. The proposed studies will identify/characterize targets which can be used to either increase or decrease this response.