Hodgkin-Huxley (HH) 模型對於電流生理學的發展有著深遠的影響。它能精確地模擬離子通道的變化。然而，隨著多年來的反覆驗證，研究人員發現HH模型亦有其局限性和不足之處。有見及此，本論文提出一個建基於變形動力學的模型，藉此以更深入的物理層面解釋Hodgkin與Huxley的實驗數據。新的模型為鉀與鈉離子通道建立了新的電導方程。在這模型的詮釋下，HH模型的鉀離子通道電導方程[附圖] 被[附圖]取代，而HH模型的鈉離子通道電導方程 [附圖] 則被 [附圖] 取而代之。縱使 n(t), m(t)和 h(t)在兩個模型中被授予不同的物理意義，但它們均是一階微分方程。此論文詳細闡述模型的建立過程及參數的推導，並論證它能準確地描繪Hodgkin與Huxley對於烏賊巨軸突的實驗數據。模型參數經由遺傳演算法優化後，新的模型不僅能夠準確描述離子通道的電導變化，還能闡述Cole-Moore shift現象。在相同強度的去極化刺激和溫度下，新的模型比HH模型能接近地模擬膜動作電位的實驗數據。 / Hodgkin-Huxley (HH) model has a profound influence on the development of electrophysiology. It is capable of modeling the transient responses of voltage-gated ion channels precisely. Nevertheless, limitations and deficiencies of the model were found as researchers conducted subsequent experiments. In this regard, a new model based on deformation kinetic has been put forth to help explaining the HH experimental data with a deeper level of physical insight. Under the proposed model, the famous HH equation [with formula] for the description of potassium conductance was replaced by [with formula] and the HH sodium conductance equation [with formula] was substituted by [with formula]. Meanwhile, n(t), m(t) and h(t) are still first order differential equations as the HH case. This thesis contributes to illustrate the capability of the new model in approximating HH’s experimental data on squids’ giant axons. Detailed derivation of the new model and identification of the parametric functions are summarized in this report. A customized genetic algorithm was utilized to optimize the model parameters. After fine tuning the new model, we are able to describe the conductance behaviors of voltage-gated ion channels closely, and manage to account for the Cole-Moore shift phenomenon. Under identical initial depolarizing stimuli and temperature as stated in HH’s experiments, close approximations of membrane action potential can also be obtained by the new model. / Detailed summary in vernacular field only. / Yu, Cheuk Him Derek. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 69-70). / Abstracts also in Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Overview of Electrophysiological Models --- p.4 / Chapter 1.2 --- The Hodgkin-Huxley Membrane Current Model --- p.4 / Chapter 1.2.1 --- Hodgkin-Huxley Potassium Channel --- p.6 / Chapter 1.2.2 --- Hodgkin-Huxley Sodium Channel --- p.8 / Chapter 1.3 --- Proliferation of the Deformation Kinetic Based Model --- p.10 / Chapter 1.4 --- Thesis Outline --- p.12 / Chapter 2 --- The Deformation Kinetic Based Model --- p.13 / Chapter 2.1 --- The Molecular Theory --- p.13 / Chapter 2.1.1 --- Application of Deformation Kinetics --- p.13 / Chapter 2.1.2 --- The Energy Function E{U+2093} (q) --- p.14 / Chapter 2.1.3 --- The Population Distribution Function P{U+2093} (N,t) --- p.17 / Chapter 2.1.4 --- Conductance Model for Voltage-gated Ion Channels --- p.18 / Chapter 2.2 --- The Approximate Solutions --- p.19 / Chapter 2.2.1 --- Approximation of the General Solution for G{U+2093} (N) --- p.19 / Chapter 2.2.2 --- Approximation of the General Solution for P{U+2093} (N,t) --- p.19 / Chapter 2.2.3 --- The Approximate Solution for Molecular g{U+2093} (t) --- p.23 / Chapter 2.2.4 --- A Convenient Form of the Approximate Solutions --- p.24 / Chapter 2.3 --- Chapter Summary --- p.25 / Chapter 3 --- Voltage-gated Ion Channel Modeling --- p.27 / Chapter 3.1 --- Voltage-gated Potassium Channel Modeling --- p.27 / Chapter 3.2 --- Voltage-gated Sodium Channel Modeling --- p.29 / Chapter 3.3 --- Chapter Summary --- p.31 / Chapter 4 --- The Parametric Functions --- p.32 / Chapter 4.1 --- The Curve Fitting References - HH Experimental Data --- p.32 / Chapter 4.2 --- Curve Fitting through Genetic Algorithm --- p.34 / Chapter 4.3 --- Functional Approximations w.r.t. HH Experimental Data --- p.37 / Chapter 4.3.1 --- Parametric Functions for Voltage-gated Potassium Channel --- p.37 / Chapter 4.3.2 --- Parametric Functions for Voltage-gated Sodium Channel --- p.39 / Chapter 4.4 --- Chapter Summary --- p.46 / Chapter 5 --- The Tracing Results --- p.47 / Chapter 5.1 --- Voltage Clamp Tracings --- p.47 / Chapter 5.1.1 --- Potassium Conductance Tracings --- p.48 / Chapter 5.1.2 --- Sodium Conductance Tracings --- p.49 / Chapter 5.2 --- Membrane Action Potential Tracings --- p.54 / Chapter 5.3 --- Propagated Action Potential Tracings --- p.56 / Chapter 5.4 --- Chapter Summary --- p.59 / Chapter 6? --- The Cole-Moore Shift Phenomenon --- p.60 / Chapter 6.1 --- Cole-Moore shift Phenomenon of Voltage-gated Potassium Channel --- p.61 / Chapter 6.2 --- Cole-Moore Shift Phenomenon of Voltage-gated Sodium Channel --- p.62 / Chapter 6.3 --- Chapter Summary --- p.64 / Chapter 7 --- Discussions --- p.65 / Conclusion --- p.67 / Future Works --- p.68 / References --- p.69 / Chapter Appendix I --- Hodgkin-Huxley’s Analysis of Voltage-gated Channels’ Voltage Clamp Data / Chapter (a) --- HH’s Analysis of Potassium Conductance Change in Voltage Clamp Experiments --- p.71 / Chapter (b) --- HH’s Analysis of Sodium Conductance Change in Voltage Clamp Experiments --- p.71 / Chapter Appendix II --- Numerical Estimations of Hodgkin-Huxley’s Experimental Data / Chapter (a) --- Numerical Estimations of Podium Conductance Change in Voltage Clamp Experiments for HH axon 17 --- p.72 / Chapter (b) --- Numerical Estimations of Sodium Conductance Change in Voltage Clamp Experiments for HH axon 17 --- p.73 / Chapter (c) --- Numerical Estimations of Membrane Action Potential with Different Initial Depolarizations for HH axon 17 --- p.74 / Chapter Appendix III --- Verification of the Replica of HH Model’s Simulations Results / Chapter (a) --- Comparison between HH Membrane Action Potential and Its Replica --- p.75 / Chapter (b) --- Comparison between HH Propagated Action Potential and Its Replica --- p.76

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Indiana University-Purdue University Indianapolis (IUPUI) / As mass production of carbon nanoparticles (CNPs) continues to rise, the likelihood of occupational and environmental exposure raises the potential for exposure‐related health hazards. Although many groups have studied the effects of CNPs on biological systems, very few studies have examined the effects of exposure of cells, tissues or organisms to low, physiologically relevant concentrations of CNPs. Three of the most common types of CNPs are single wall nanotubes (SWNT), multi wall nanotubes (MWNT) and fullerenes (C60). We used electrophysiological techniques to test the effects of CNP exposure (40 μg/cm2 – 4 ng/cm2) on barrier function and hormonal responses of well characterized cell lines representing barrier epithelia from the kidney (mpkCCDcl4) and airways (Calu‐3). mpkCCDcl4 is a cell line representing principal cell type that lines the distal nephron in an electrically tight epithelia that aids in salt and water homeostasis and Calu‐3 is one of the few cell lines that produces features of a differentiated, functional human airway epithelium in vivo. These cell lines respond to hormones that regulate salt/water reabsorption (mpkCCDcl4) and chloride secretion (Calu‐3). In mpkCCDcl4 cells, after 48 hour exposure, the transepithelial electrical resistance (TEER) was unaffected by high concentrations (40 – 0.4 μg/cm2) of C60 or SWNT while lower, more relevant levels (< 0.04 μg/cm2) caused a decrease in TEER. MWNT decreased TEER at both high and low concentrations. CNT exposure for 48 hour did not change the transepithelial ion transport in response to anti‐diuretic hormone (ADH). In Calu‐3 cells, after 48 h of exposure to CNPs, fullerenes did not show any effect on TEER whereas the nanotubes significantly decreased TEER over a range of concentrations (4 μg/cm2‐0.004 ng/cm2). The ion transport response to epinephrine was also significantly decreased by the nanotubes but not by fullerenes. To look at the effect of exposure times, airway cells were exposed to same concentrations of CNPs for 24 and 1h. While the 48 h and 24 h exposures exhibited similar effects, there was no effect seen after 1h in terms of TEER or hormonal responses. In both the cell lines the magnitude of the transepithelial resistance change does not indicate a decrease in cellular viability but would be most consistent with more subtle changes (e.g., modifications of the cytoskeleton or changes in the composition of the cellular membrane). These changes in both the cell lines manifested as an inverse relationship with CNP concentration, were further corroborated by an inverse correlation between dose and changes in protein expression as indicated by proteomic analysis. These results indicate a functional impact of CNPs on epithelial cells at concentrations lower than have been previously studied and suggest caution with regard to increasing CNP levels due to increasing environmental pollution.

Indiana University-Purdue University Indianapolis (IUPUI) / Carbon nanotubes (CNTs) are one of the most common nanoparticles (NP) found in workplace air. Therefore, there is a strong chance that these NP will enter the human body. They have similar physical properties to asbestos, a known toxic material, yet there is limited evidence showing that CNTs may be hazardous to human barrier epithelia. In previous studies done in our laboratory, the effects of CNTs on the barrier function in the human airway epithelial cell line (Calu-3) were measured. Measurements were done using electrophysiology, a technique which measures both transepithelial electrical resistance (TEER), a measure of monolayer integrity, and short circuit current (SCC) which is a measure of vectorial ion transport across the cell monolayer. The research findings showed that select physiologically relevant concentrations of long single-wall (SW) and multi-wall (MW) CNTs significantly decreased the stimulated SCC of the Calu-3 cells compared to untreated cultures. Calu-3 cells showed decreases in TEER when incubated for 48 hours (h) with concentrations of MWCNT ranging from 4µg/cm2 to 0.4ng/cm2 and SWCNT ranging from 4µg/cm2 to 0.04ng/cm2. The impaired cellular function, despite sustained cell viability, led us to investigate the mechanism by which the CNTs were affecting the cell membrane. We investigated the interaction of short MWCNTs with model lipid membranes using an ion channel amplifier, Planar Bilayer Workstation. Membranes were synthesized using neutral diphytanoylphosphatidylcholine (DPhPC) and negatively charged diphytanoylphosphatidylserine (DPhPS) lipids. Gramicidin A (GA), an ion channel reporter protein, was used to measure changes in ion channel conductance due to CNT exposures. Synthetic membranes exposed to CNTs allowed bursts of currents to cross the membrane when they were added to the membrane buffer system. When added to the membrane in the presence of GA, they distorted channel formation and reduced membrane stability.

Indiana University-Purdue University Indianapolis (IUPUI) / Gender differences in the basal function of autonomic cardiovascular control are well documented. Consistent baroreflex (BRx) studies suggest that women have higher tonic parasympathetic cardiac activation compared to men. Later in life and concomitant with menopause, a significant reduction in the capacity of the BRx in females increases their risk to develop hypertension, even exceeding that of age-matched males. Loss of sex hormones is but one factor. In female rats, we previously identified a distinct myelinated baroreceptor (BR) neuronal phenotype termed Ah-type, which exhibits functional dynamics and ionic currents that are a mix of those observed in barosensory afferents functionally identified as myelinated A-type or unmyelinated C-type. Interestingly, Ah-type afferents constitute nearly 50% of the total population of myelinated aortic BR in female but less than 2% in male rat. We hypothesized that an afferent basis for sexual dimorphism in BRx function exists. Specifically, we investigated the potential functional impact Ah-type afferents have upon the aortic BRx and what changes, if any, loss of sex hormones through ovariectomy brings upon such functions. We assessed electrophysiological and reflexogenic differences associated with the left aortic depressor nerve (ADN) from adult male, female, and ovariectomized female (OVX) Sprague-Dawley rats. Our results revealed sexually dimorphic conduction velocity (CV) profiles. A distinct, slower myelinated fiber volley was apparent in compound action potential (CAP) recordings from female aortic BR fibers, with an amplitude and CV not observed in males. Subsequent BRx studies demonstrated that females exhibited significantly greater BRx responses compared to males at myelinated-specific intensities. Ovariectomy induced an increased overall temporal dispersion in the CAP of OVX females that may have contributed to their attenuated BRx responses. Interestingly, the most significant changes in depressor dynamics occurred at electrical thresholds and frequencies most closely aligned with Ah-type BR fibers. Collectively, we provide evidence that, in females, two anatomically distinct myelinated afferent pathways contribute to the integrated BRx function, whereas in males only one exists. These functional differences may partly account for the enhanced control of blood pressure in females. Furthermore, Ah-type afferents may provide a neuromodulatory pathway uniquely associated with the hormonal regulation of BRx function.