Brain-Derived Neurotrophic Factor and Sympathoexcitation in Chronic Heart Failure

 描述（由申请人提供）：该项目的主要目的是确定脑源性神经营养因子（BDNF）在调节交感神经活动（SNA）和K+通道活动以响应血管紧张素II（Ang II）中的作用及其在心血管疾病状态中的潜在作用，例如慢性心力衰竭（CHF）。心血管疾病是全球发病率和死亡率的主要原因，CHF是其中大量病例的原因。虽然有许多因素影响CHF的结果，SNA的增加，这是依赖于特定的脑干神经元的活动和敏感性，与并发症的增加和CHF进展期间的死亡率较高。神经元的放电敏感性取决于外向K+电流的大小，当外向K+电流降低时，外向K+电流促进兴奋性。CHF动物脑内升高的血管紧张素（Ang）II和活性氧等因子可降低K+电流。在寻找可能影响CHF交感神经流出的其他因素时，我们研究了脑源性神经营养因子（BDNF）的作用，BDNF也被证明可以抑制K+电流，并可能与Ang II相互作用。根据以前的研究，BDNF已被集中，这是可能的，这种蛋白质可能有助于交感神经兴奋在CHF。因此，基于文献和我们的初步实验的证据，我们假设在Ang II升高的状态下，如CHF，增加的神经元BDNF表达和信号沿着会聚通路有助于抑制K+电流并促进神经元兴奋性。为了研究这一假设，提出了三个具体目标。在特定目标1中，将在细胞培养和CHF大鼠模型中研究Ang II和BDNF之间在引起会聚信号传导途径的激活增加和ROS水平升高方面的联系。在具体目标2中，膜片钳电生理学实验将研究Ang II和BDNF在神经元细胞系和原代神经元培养物中降低K+电流和增加神经元兴奋性方面相互作用的潜在位点。在具体目标3中，将BDNF或BDNF信号传导拮抗剂的直接中枢给药给予CHF大鼠模型，以研究该因子对CHF进展的贡献。一个全面的博士前培训计划描述与锐化和扩大申请人的研究技能的目标。

 DESCRIPTION (provided by applicant): The primary objective of this project is to determine the role of Brain-Derived Neurotrophic Factor (BDNF) in modulation of sympathetic nerve activity (SNA) and K+ channel activity in response to Angiotensin II (Ang II) and its potential rol in cardiovascular disease states such as chronic heart failure (CHF). Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with CHF contributing to a substantial number of these cases. Although numerous factors influence the outcome of CHF, increases in SNA, which is dependent on the activity and sensitivity of specific brainstem neurons, are associated with an increase in complications and a higher mortality rate during the progression of CHF. The discharge sensitivity of neurons depends on the magnitude of outward K+ currents, which when decreased promote excitability. Factors such as Angiotensin (Ang) II and reactive oxygen species, which are elevated in the brains of animals with CHF, can decrease K+ currents. In a search for additional factors that may impact sympathetic outflow in CHF, we examined the role of Brain-Derived Neurotrophic Factor (BDNF) which has also been shown to suppress K+ currents and may interact with Ang II. Based on previous studies in which BDNF has been given centrally it is likely that this protein may contribute to sympathoexcitation in CHF. Therefore, based on evidence from the literature and our preliminary experiments, we hypothesize that in states where Ang II is elevated, such as CHF, increased neuronal BDNF expression and signaling along convergent pathways contributes to the suppression of K+ currents and promotes neuronal excitability. To investigate this hypothesis three specific aims are proposed. In Specific Aim 1, the link between Ang II and BDNF in causing increased activation of convergent signaling pathways and elevated ROS levels will be investigated in cell culture and a rat model of CHF. In Specific Aim 2, patch clamp electrophysiology experiments will investigate the potential sites of interaction between Ang II and BDNF in decreasing K+ currents and increasing neuronal excitability in neuronal cell lines and primary neuronal cultures. In Specific Aim 3, direct central administration of BDNF or antagonists to BDNF signaling will be administered to a rat model of CHF to investigate the contribution of this factor to the progression of CHF. A comprehensive pre-doctoral training program is described with the goal of sharpening and broadening research skills of the applicant.