Indiana University-Purdue University Indianapolis (IUPUI) / Many signaling pathways which are classically understood for their roles in early development are also known to be involved in tissue maintenance and adult energy homeostasis. Furthermore, dysfunction of these signaling pathways results in human diseases such as cancer. An in depth understanding of how developmentally important signaling pathways function in the adult will provide mechanistic insights into disease and potential new therapeutic targets. Here in Chapter 1, the Wnt, fibroblast growth factor (FGF), and Hedgehog (Hh) signaling pathways are discussed and examples of their relevance in development, adult homeostasis, and disease are provided. Wnt signaling provides an example of this concept as it has well described roles during both development and adult metabolism. Work included in Chapter 2, investigates the regulation of adult energy homeostasis by a member of the endocrine FGF family, FGF19. The three endocrine FGFs, FGF19 (FGF15 in mice), FGF21, and FGF23 have well described roles in the regulation of metabolic processes in adults. While FGF23 is primarily involved in the regulation of phosphate and vitamin D homeostasis, FGF19 and FGF21 have shown similar pharmacological effects on whole body metabolism. Here, the importance of adaptive thermogenesis for the pharmacological action of FGF19 is explored. Using UCP1KO animals we show that whole-body thermogenesis is dispensable for body weight loss following FGF19 treatment. Finally, the potential involvement of Hh signaling in mediating the hyperphagia driven obesity observed in certain ciliopathies is explored in Chapter 3. Emerging evidence suggests cilia play an important role in the regulation of feeding behavior. In mammals, the hedgehog pathway is dependent on the primary cilium as an organizing center and defects in hedgehog signaling share some clinical symptoms of ciliopathies. Here, we characterized the expression of core pathway components in the adult hypothalamus. We show that neurons within specific nuclei important for regulation of feeding behavior express Hh ligand and members of its signaling pathway. We also demonstrate that the Hh pathway is transcriptionally upregulated in response to an overnight fast. This work provides an important foundation for understanding the functional role of Hh signaling in regulation of energy homeostasis. In its entirety, this work highlights the emerging clinical relevance of developmentally critical pathways in diseases associated with dysfunction of adult tissue homeostasis, such as obesity.

After more than a century, there are no analytical solutions for the Navier-Stokes equations to describe complex fluid behavior, and we often resort to different computational methods to find solutions under specific conditions. In particular, to address many biological questions, we need to use techniques which are accurate at the mesoscale regime and computationally efficient, since atomistic simulations are still incredibly computationally costly, and continuum methods based on Navier-Stokes present challenges with complicated moving boundaries, in the presence of fluctuations. Here, we use a novel particle-based coarse-grained method, known as MPCD, to study ciliated swimmers. Using experimentally measured beating patterns, we show how we recapitulate the emergence of metachronal waves (MCW) on planar surfaces, and present new results on curved surfaces. To quantitatively study these waves, we also analyzed their effect on beating intervals, energy fluctuations, and fluid motion. We then extended our model to realistic cellular geometries, using experimentally obtained Basal Bodies locations.\par In the second part of our study, we focused on the intracellular fluid motion, neglecting hydrodynamic interactions. We developed the Digital Confocal Microscopy Suite (DCMS) that can run on multiple platforms using GPUs and can input realistic cell shapes and optical properties of the confocal microscope. It has this ability to simulate both (Fluorescence Recovery After Photobleaching) FRAP and Fluorescence Correlation Spectroscopy (FCS) experiments, as well as the capability to model photo-switching of fluorophores, acquisition photo-bleaching, and reaction-diffusion systems. With this platform, in collaboration with the Vidali Lab, we were able to elucidate the role of boundaries in interpreting FRAP experiments in \textit{moss} and estimate the binding rates of myosin XI.

Indiana University-Purdue University Indianapolis (IUPUI) / Bone loss diseases, including osteoporosis affect millions of people worldwide. Understanding the underlying mechanisms behind bone homeostasis and adaptation is essential to uncovering new therapeutic targets for the prevention and treatment of bone loss diseases. Primary cilia have been implicated in the development and mechanosensation of various tissue types, including bone. The goal of the studies outlined in this thesis is to determine the mechanosensory role of primary cilia in bone cell function, bone growth, and adaptation. This goal was achieved by exploring two specific scenarios. In the first study, mice models with conditional knockouts of MKS5, a ciliary protein, in osteocytes were utilized to demonstrate that dysfunctional primary cilia in those cells result in impaired loading-induced bone formation. The hypothesis tested is that the existence of functioning primary cilia on osteocytes is crucial for proper bone adaptation following stress. The results of this study support the hypothesis, with the conditional knockout mice showing significantly lower loading-induced bone formation compared to controls. The second study highlighted the importance of the osteoblast primary cilia in bone growth by using mice models with osteoblast-specific deletion of the cilia. The hypothesis tested is that the presence of the primary cilia is crucial for proper bone growth. The results show that conditional knockout mice have lower body weights, decreased femur length, and a significantly lower rate of bone formation, confirming that the primary cilia play a great role in bone growth and development. This study has highlighted the role of primary cilia in bone health and this topic merits further investigation.

Adula (Botula) falcata Gould (Soot-Ryen, 1955) lives commonly as a byssally attached rock borer in soft mudstone reefs at Bolinas and Moss Beach, California (Figure 1). Keen (1963) reports that Adula falcata has been collected from the intertidal to a depth of ten fathoms. Its distribution is from Coos Bay, Oregon, to Cape San Lucas, Lower California (Hertlein and Strong, 1946), and collection data indicate a range as far south as Peru (Soot-Ryen, 1955). While is possesses the protective advantage of living cryptically, Adula falcata is subjected to an environmental stress not faced by epifaunal mytillids; namely, it must function within a burrow into which sediment material is being continuously deposited from both particle laden water passing over its burrow entrance and the mudstone byproducts of its own mechanical boring. The following is a comparative study on the ciliary mechanisms of feeding, digestion, and sediment removal in Adula falcata. Sediment removal could hardly be considered separately from feeding and digestion, as it is during these latter two processes that sediment is resolved from potential food material and extruded from the burrow. Aside from publications of a purely taxonomic nature, the sole direct references to Adula falcata have been in Lloyd’s (1897) observations on lamellibranch rock boring and Yonge’s (1955) comprehensive work on the adaptation and evolution of the boring habit in the Family Mytilidae. It was, in fact, Yonge’s observations on the role of Figure 1. A lateral view of the burrow of Adula falcata. The mudstone burrow has been cracked open to expose the left side of the enclosed bivalve. This byssally attached mussel had withdrawn from the head of the excavation and had extended its siphonal process for feeding. Other noteworthy features include the furry incrustation on the posterodorsal triangle of the valve and a partially eroded umbone.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21262号 / 医博第4380号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 伊達 洋至, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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