Cellular and molecular regulation of skeletal muscle regeneration

Skeletal muscle regeneration provides a powerful model to study the cellular and molecular mechanism governing stem cell function since the whole process is mediated by a population of muscle-resident stem cells called satellite cells. The overall aim of this dissertation is to explore the roles of Notch signaling and a novel gene (Bex1) in satellite cell function and skeletal muscle regeneration. ^ The first part of this thesis is to examine how the Notch signaling pathway regulates the satellite cell self-renewal in a disease model. The MDX mouse is a well-established model for Duchenne muscular dystrophy (DMD) and characterized by progressive muscle degeneration and regeneration. Here, I showed that the number and activity of satellite cells in MDX mice were reduced in an age-dependent manner. Given that satellite cells can self-renew to maintain the homeostasis, I further demonstrated that the self-renewal capacity was defective in MDX mice. As the Notch signaling pathway has been reported to regulate satellite cell quiescence, I continued to confirmed that the self-renewal defect was due to the perturbed Notch in MDX satellite cells. Furthermore, I attempted to genetically activate the Notch signaling pathway in satellite cells to improve muscle regeneration in MDX mice. Surprisingly, although the Notch activation increased the satellite cell number and rescued the self-renewal defects, it did not contribute to muscle regeneration. Nevertheless, this study extends our understanding of the Notch signaling pathway in the activity of satellite cells and in muscle regeneration. ^ The second part of this dissertation focuses on the roles of Bex1 in muscle regeneration. Bex1 is a novel gene with unknown functions in skeletal muscles. I first found that Bex1 was temporarily expressed in myogenic cells with a nuclear-cytoplasmic trafficking pattern during embryonic development and postnatal regeneration. The exclusive expression of Bex1 in differentiated myocytes suggests that Bex1 may play unknown roles in regulating myogenic differentiation. Previous studies suggested that Bex1 could regulate neuron cell cycle withdrawal. Here I demonstrated that Bex1 participated in myogenic differentiation independent of the cell cycle withdrawal. Instead, I showed that Bex1 promoted myoblast-myotube fusion in vitro and the regulation was independent of myogenic differentiation per se. However, Bex1 knockout mice appeared normal and did not exhibit obvious defects in the skeletal muscle. This study characterized the novel function of Bex1 in the myogenesis and facilitated the understanding of myoblast fusion process. ^ Collectively, the findings about how Notch signaling and Bex1 regulate the function of satellite cells as well as muscle regeneration derived from this dissertation will extend our understanding of the cellular and molecular mechanism of muscle regeneration. Consequently, this dissertation can shed light on providing therapeutic avenues for the prevention and treatment of muscle diseases

Stability and related zero viscosity limit of steady plane Poiseuille-Couette flows with no-slip boundary condtion

We prove the existence and stability of smooth solutions to the steady Navier-Stokes equations near plane Poiseuille-Couette flow. Consequently, we also provide the zero viscosity limit of the 2D steady Navier-Stokes equations to the steady Euler equations. First, in the absence of any external force, we prove that there exist smooth solutions to the steady Navier-Stokes equations which are stable under infinitesimal perturbations of plane Poiseuille-Couette flow. In particular, if the basic flow is the Couette flow, then we can prove that the flow is stable for any finite perturbation small enough. Moreover, we also show that, if we put a proper external force to control the flow, then we can also obtain a large class of smooth solution of the steady Navier-Stokes equations which is stable for infinitesimal perturbation of the external force. Finally, based on the same linear estimates, we establish the zero viscosity limit of all the solutions obtained above to the solutions of the Euler equations

The use of indicators for unobservable product qualities: inferences based on consumer sorting

Using the dietary supplement black cohosh to demonstrate our method, we employ data on a product characteristic unobservable to consumers to decompose the contribution to consumers’ valuations of observable characteristics into surrogate indicator and direct components. Because consumers are not all “expert appraisers” of the unobservable characteristic, the measured relationship of indicators to the unobservable quality is generally not the one consumers perceive. Consequently, biases that depend upon the nature of consumers’ ineptitude are introduced into the component estimation. The researcher’s inference problem is solved by recognizing that consumers with greater appraisal expertise sort disproportionately to higher quality products. This enables feasible measurement of inept consumers’ relative valuations and conjectures through separate hedonic estimation on high- and low-quality product subsamples. We find that, relative to experts, inept consumers likely underestimate the value of most observable characteristics in indicating black cohosh product authenticity; however they overweight online product ratings.hedonic analysis; surrogate indicators; asymmetric information; pricing strategy; product strategy

Design and Applications of Phosphine Ligands to Transition Metal-Catalyzed Reactions

Ph.DDOCTOR OF PHILOSOPH

Measurement of and Factors Associated with the Anterior Chamber Volume in Healthy Chinese Adults

Purpose. To measure the anterior chamber volume (ACV) and determine factors associated with the ACV in healthy Chinese adults. Methods. In this cross-sectional study, we used swept-source optical coherence tomography (SS-OCT) to measure ACV and other anterior segment parameters. Factors associated with ACV were also determined. Results. A total of 313 healthy Chinese adults were enrolled. The anterior segment parameters, including ACV, could be measured by SS-OCT with excellent repeatability and reproducibility. There was a significant difference between the horizontal and vertical anterior chamber widths (ACW) (P<0.05), with a mean difference of 390 μm. The ACV (mean 153.83±32.42 mm3) was correlated with most of the anterior segment parameters, especially anterior chamber depth (ACD), which accounted for about 85% of the variation of ACV. Most of the anterior segment parameters were significantly correlated with age, and the relative changes in ACV and ACD were greatest in subjects aged 41–50 years. Conclusion. ACV was correlated with most of the anterior segment parameters measured in this study, particularly ACD. The relatively large difference between horizontal and vertical ACW suggests that the ACV could and should be measured using multiple OCT scans

PPARdelta Regulates Satellite Cell Proliferation and Skeletal Muscle Regeneration

Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play important roles in development and energy metabolism. Whereas PPARdelta has been shown to regulate mitochondrial biosynthesis and slow-muscle fiber types, its function in skeletal muscle progenitors (satellite cells) is unknown. Since constitutive mutation of Ppardelta leads to embryonic lethality, we sought to address this question by conditional knockout (cKO) of Ppardelta using Myf5-Cre/Ppardeltaflox/flox alleles to ablate PPARdelta in myogenic progenitor cells. Although Ppardelta-cKO mice were born normally and initially displayed no difference in body weight, muscle size or muscle composition, they later developed metabolic syndrome, which manifested as increased body weight and reduced response to glucose challenge at age nine months. Ppardelta-cKO mice had 40% fewer satellite cells than their wild-type littermates, and these satellite cells exhibited reduced growth kinetics and proliferation in vitro. Furthermore, regeneration of Ppardelta-cKO muscles was impaired after cardiotoxin-induced injury. Gene expression analysis showed reduced expression of the Forkhead box class O transcription factor 1 (FoxO1) gene in Ppardelta-cKO muscles under both quiescent and regenerating conditions, suggesting that PPARdelta acts through FoxO1 in regulating muscle progenitor cells. These results support a function of PPARdelta in regulating skeletal muscle metabolism and insulin sensitivity, and they establish a novel role of PPARdelta in muscle progenitor cells and postnatal muscle regeneration

PPARδ regulates satellite cell proliferation and skeletal muscle regeneration

Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play important roles in development and energy metabolism. Whereas PPARδ has been shown to regulate mitochondrial biosynthesis and slow-muscle fiber types, its function in skeletal muscle progenitors (satellite cells) is unknown. Since constitutive mutation of Pparδ leads to embryonic lethality, we sought to address this question by conditional knockout (cKO) of Pparδ using Myf5-Cre/Pparδflox/flox alleles to ablate PPARδ in myogenic progenitor cells. Although Pparδ-cKO mice were born normally and initially displayed no difference in body weight, muscle size or muscle composition, they later developed metabolic syndrome, which manifested as increased body weight and reduced response to glucose challenge at age nine months. Pparδ-cKO mice had 40% fewer satellite cells than their wild-type littermates, and these satellite cells exhibited reduced growth kinetics and proliferation in vitro. Furthermore, regeneration of Pparδ-cKO muscles was impaired after cardiotoxin-induced injury. Gene expression analysis showed reduced expression of the Forkhead box class O transcription factor 1 (FoxO1) gene in Pparδ-cKO muscles under both quiescent and regenerating conditions, suggesting that PPARδ acts through FoxO1 in regulating muscle progenitor cells. These results support a function of PPARδ in regulating skeletal muscle metabolism and insulin sensitivity, and they establish a novel role of PPARδ in muscle progenitor cells and postnatal muscle regeneration