TRK RECEPTORS AND NEUROTROPHINS

这项建议涉及通过分析不同的小鼠模型来理解神经发育的方法，继续研究神经营养因子(NTF)及其受体。Trk家族受体酪氨酸激酶及其配体NTF与神经元的存活和分化密切相关。NTFS已被认为是治疗阿尔茨海默病和肌萎缩侧索硬化症等神经退行性疾病以及脊髓损伤的潜在药物。在此之前，我们培育了多种Trk受体&NTF突变小鼠。对这些小鼠的研究为了解神经营养因子在神经元存活中的体内功能提供了有价值的信息。我们建议继续这些研究&第一个目标是继续研究NTF在感觉神经元发育和存活中的作用。我们将进一步利用这些突变小鼠来继续对NTF在嗅觉和味觉系统发育中的需求进行初步分析。我们还将对我们的空trkC和NT-3突变体与Kinase零trkC突变体进行详细的比较分析。这些建议的研究首次直接涉及截断受体的体内功能。在第二个目标中，我们将确定调节NGF受体TrkA的决定因素。这种增强子分析将提供有关调节神经营养素受体的上游分子&发育中的神经系统的新信息。在第三个目标中，我们将利用TrkA增强子的存在，在体内进行TrkA受体的结构/功能分析。我们将在体外突变TrkA的细胞内信号决定因素，并将突变的转基因受体引入TrkA-/-小鼠。将对转基因胚胎进行分析，以挽救几个定义的参数。这一方法将揭示体内神经元存活和分化的生理学相关信号效应器。NTF基因敲除研究的一个局限性是出生后早期死亡。这就排除了对成人功能的分析。在第四个目标中，我们建议完成我们正在进行的TrkB和BDNF的条件淘汰策略，这将使我们能够扩大我们的研究。

This proposal concerns the continued study of neurotrophins (NTFs) and their receptors, via the analysis of diverse mouse models as a means to understand neural development. Trk family receptor tyrosine kinases and their ligands, the NTFs, have been implicated in neuronal survival and differentiation. NTFs have been considered as potential therapeutic agents for neurodegenerative diseases including Alzheimer's & ALS as well as for spinal cord injury. In the previous period, we generated a variety of Trk receptor & NTF mutant mice. Study of these mice has provided valuable information regarding the in vivo function of NTFs in neuronal survival. We proposed to continue these studies &in the First Aim will continue to study NTF function in sensory neuron development and survival. We will further exploit these mutant mice to continue preliminary analysis of NTF requirement in development of the olfactory, and gustatory systems. We will also perform a detailed comparative analysis of our null trkC & NT-3 mutants with a Kinase null trkC mutant. These proposed studies for the first time directly address the in vivo function of truncated receptors. In the Second Aim we will identify the determinants that regulate the NGF receptor, TrkA. This enhancer analysis will provide novel information about the upstream molecules that regulate neurotrophin receptors & the developing nervous system. In the third aim, we will exploit the existence of a TrkA enhancer, to perform structure/function analysis of the TrkA receptor in vivo. We will in vitro mutate intracellular signaling determinants of TrkA and introduce mutated transgenic receptors into the TrkA-/- mouse. Transgenic embryos will be analyzed for rescue of several defined parameters. This approach will reveal physiologically relevant signaling effectors for survival and differentiation of neurons in vivo. A limitation of NTF knockout studies has been early postnatal lethality. This precludes analysis of function in the adult. In the Fourth Aim, we propose to complete our ongoing conditional Knock Out strategies for TrkB and BDNF which will enable us to expand our studies.