Cadmium-induced changes in sonic Hedgehog signaling and T cell development during

描述（由申请人提供）：Sonic Hedgehog （SHh）是一种重要的信号分子，有助于协调胚胎发育，最近被证明在成人生活和胎儿发育期间也在免疫细胞的更新中起作用。镉（Cd）是一种重金属，既是一种环境污染物，也是香烟烟雾的重要成分。Cd也是一种已知的哺乳动物致畸原，可导致啮齿动物前肢畸形。虽然作为一种致畸原被广泛研究，但只有最近的证据提供了这种致畸效应的机制，即Cd处理的水坝后代中的Sonic Hedgehog （sHh）信号发生改变。本申请申请资金收集初步数据，以连接Cd在胎儿发育期间改变胸腺细胞发育的潜力。这项工作的重要性在于，它不仅为了解SHh在胎儿胸腺发育中的作用提供了一个有价值的探针，而且还确定了在子宫内暴露于Cd的后代的潜在风险。提出了一个特定的目标：确定产前Cd对SHh信号的破坏会改变小鼠胎儿的T细胞发育。这一特定的目的是验证产前Cd暴露会降低SHh水平从而降低新生儿胸腺细胞双阳性百分比的假设。

DESCRIPTION (provided by applicant): Sonic Hedgehog (SHh), an important signaling molecule that helps orchestrate embryonic development, has recently been shown to also function in the renewal of immune cells during adult life as well as during fetal development. Cadmium (Cd) is a heavy metal that is both an environmental contaminant as well as a significant component of cigarette smoke. Cd is also a known mammalian teratogen that causes forelimb ectrodactyly in rodents. Although extensively studied as a teratogen, only very recent evidence provides a mechanism for this teratological effect, that is, that Sonic Hedgehog (sHh) signaling is altered in the offspring of Cd treated dams. This application requests funds to collect preliminary data to connect the potential of Cd to alter the development of thymocytes during fetal development. The importance of this work is both to develop a valuable probe to understand the role of SHh in fetal thymic development as well as determine the potential risk for the offspring exposed to Cd in utero. One specific aim is proposed: Establish that prenatal Cd disruption of SHh signaling alters T cell development in the mouse fetus. This specific aim is to test the hypothesis that prenatal Cd exposure will lower SHh levels resulting in a lower percentage of double positive thymocytes in the newborn.