Neurogranin controls the spatiotemporal pattern of postsynaptic Ca2+/CaM signaling.

Neurogranin (Ng) is a postsynaptic IQ-motif containing protein that accelerates Ca(2+) dissociation from calmodulin (CaM), a key regulator of long-term potentiation and long-term depression in CA1 pyramidal neurons. The exact physiological role of Ng, however, remains controversial. Two genetic knockout studies of Ng showed opposite outcomes in terms of the induction of synaptic plasticity. To understand its function, we test the hypothesis that Ng could regulate the spatial range of action of Ca(2+)/CaM based on its ability to accelerate the dissociation of Ca(2+) from CaM. Using a mathematical model constructed on the known biochemistry of Ng, we calculate the cycle time that CaM molecules alternate between the fully Ca(2+) saturated state and the Ca(2+) unbound state. We then use these results and include diffusion of CaM to illustrate the impact that Ng has on modulating the spatial profile of Ca(2+)-saturated CaM within a model spine compartment. Finally, the first-passage time of CaM to transition from the Ca(2+)-free state to the Ca(2+)-saturated state was calculated with or without Ng present. These analyses suggest that Ng regulates the encounter rate between Ca(2+) saturated CaM and its downstream targets during postsynaptic Ca(2+) transients.

Respiratory rhythm generation: A modeling study of the respiratory central pattern generator and the phrenic motor neuron

The respiratory central pattern generator is a collection of medullary neurons that generates the rhythm of respiration. The respiratory central pattern generator feeds phrenic motor neurons, which, in turn, drive the main muscle of respiration, the diaphragm. The purpose of this thesis is to understand the neural control of respiration through mathematical models of the respiratory central pattern generator and phrenic motor neurons. ^ We first designed and validated a Hodgkin-Huxley type model that mimics the behavior of phrenic motor neurons under a wide range of electrical and pharmacological perturbations. This model was constrained physiological data from the literature. Next, we designed and validated a model of the respiratory central pattern generator by connecting four Hodgkin-Huxley type models of medullary respiratory neurons in a mutually inhibitory network. This network was in turn driven by a simple model of an endogenously bursting neuron, which acted as the pacemaker for the respiratory central pattern generator. Finally, the respiratory central pattern generator and phrenic motor neuron models were connected and their interactions studied. ^ Our study of the models has provided a number of insights into the behavior of the respiratory central pattern generator and phrenic motor neurons. These include the suggestion of a role for the T-type and N-type calcium channels during single spikes and repetitive firing in phrenic motor neurons, as well as a better understanding of network properties underlying respiratory rhythm generation. We also utilized an existing model of lung mechanics to study the interactions between the respiratory central pattern generator and ventilation. ^

Comparative studies of Hox genes in mammalian limb and vertebral pattern formation

Divergence of anterior-posterior (AP) limb pattern and differences in vertebral column morphology are the two main examples of mammalian evolution. The Hox genes (homeobox containing gene) have been implicated in driving evolution of these structures. However, regarding Hox genes, how they contribute to the generation of mammalian morphological diversities, is still unclear. Implementing comparative gene expression and phenotypic rescue studies for different mammalian Hox genes could aid in unraveling this mystery. In the first part of this thesis, the expression pattern of Hoxd13 gene, a key Hox gene in the establishment of the limb AP pattern, was examined in developing limbs of bats and mice. Bat forelimbs exhibit a pronounced asymmetric AP pattern and offer a good model to study the molecular mechanisms that contribute to the variety of mammalian limbs. The data showed that the expression domain of bat Hoxd13 was shifted prior to the asymmetric limb plate expansion, whereas its domain in mice was much more symmetric. This finding reveals a correlation between the divergence of Hoxd13 expression and the AP patterning difference in limb development. The second part of this thesis details a phenotypic rescue approach by human HOXB1-9 transgenes in mice with Hoxb1-9 deletion, The mouse mutants displayed homeosis in cervical and anterior thoracic vertebrae. The human transgenes entirely rescued the mouse mutants, suggesting that these human HOX genes have similar functions to their mouse orthologues in anterior axial skeletal patterning. The anterior expressing human HOXB transgenes such as HOXB1-3 were expressed in the mouse embryonic trunk in a similar manner as their murine orthologues. However, the anterior boundary of human HOXB9 expression domain was more posterior than that of the mouse Hoxb9 by 2-3 somites. These data provide the molecular support for the hypothesis that Hox genes are responsible for maintaining similar anterior axial skeletal architectures cervical and anterior thoracic regions, but different architectures in lumbar and posterior thoracic regions between humans and mice. ^

RELATION OF TYPE OF REPORTED ILLNESSES TO PATTERN OF USE OF THE STUDENT HEALTH CENTER BY THE INTERNATIONAL STUDENTS AT TEXAS SOUTHERN UNIVERSITY, HOUSTON, TEXAS

The state of knowledge on the relation of stress factors, health problems and health service utilization among university students is limited. Special problems of stress exist for the international students due to their having to adjust to a new environment. It is this latter problem area that provides the focus for this study. Recognizing there are special stress factors affecting the international students, it is first necessary to see if the problems of cultural adaptation affect them to any greater degree than American students attending the same university.^ To make the comparison, the study identified a number of health problems of both American and international students and related their frequency to the use of the Student Health Center. The expectation was that there would be an association between the number of health problems and the number of life change events experienced by these students and between the number of health problems and stresses from social factors. It was also expected that the number of health problems would decline with the amount of social support.^ The population chosen were students newly enrolled in Texas Southern University, Houston, Texas in the Fall Semester of 1979. Two groups were selected at random: 126 international and 126 American students. The survey instrument was a self-administered questionnaire. The response rate was 90% (114) for the international and 94% (118) for the American students.^ Data analyses consisted of both descriptive and inferential statistics. Chi-squares and correlation coefficients were the statistics used in comparing the international students and the American students.^ There was a weak association between the number of health problems and the number of life change events, as reported by both the international and the American students. The study failed to show any statistically significant association between the number of stress from social factors and the number of health problems. It also failed to show an association between the number of health problems and the amount of social support. These findings applied to both the international and the American students.^ One unexpected finding was that certain health problems were reported by more American than international students. There were: cough, diarrhea, and trouble in sleeping. Another finding was that those students with health insurance had a higher level of utilization of the Health Center than those without health insurance. More international than American students utilized the Student Health Center.^ In comparing the women students, there was no statistical significant difference in their reported fertility related health problems.^ The investigator recommends that in follow-up studies, instead of grouping all international students together, that they be divided by major nationalities represented in the student body; that is, Iranians, Nigerians and others. ^