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Basic Science Laboratory

Staff


L. Darryl Quarles, MD, Director

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Zhousheng Xiao, PhD

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Min Pi, PhD

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Xiaobin Han, MD, PhD, MBA

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Additional Staff Members

Jinsong Huang, PhD
Research associate in the Lab. He is mainly working BXD bone project as well as polycystin-1 and FGF23 projects. He is responsible for bone histology, bone histomorphometry, and micro-CT 3D images analyses. He also assists in data analysis, interpretation of data, and generating manuscripts for publications.

Li Cao, BS
Senior Research Technician in the Lab. She is in charge of all mouse colonies maintenance, animal breeding, tail clips and PCR genotyping. She is also responsible for mouse datasheet management, time-pregnancy, bone and other tissue sample collections at the endpoint of each experiment. She will also order laboratory supplies, maintain primary osteoblast and osteocyte cell lines, and assist other members of group when necessary.

Keiichi Sumida, MD
Postdoc Visiting Scholar

Our Basic Science Laboratory is currently investigating the local and systemic factors that regulate FGF23 gene transcription and the molecular mechanisms mediating the end-organ effects of FGF23 in the kidney and other tissues.

We also discovered that GPRC6A, an amino-acid, calcium, testosterone and osteocalcin sensing G-protein coupled receptor, is involved in the pathogenesis of multiple metabolic abnormalities, including osteopenia, glucose intolerance, insulin resistance, loss of muscle mass and obesity in mice lacking GPRC6A.  It is being proposed that GPRC6A integrates the functions of bone, fat, and muscle, as well as other tissues to regulate body composition and energy metabolism in response to nutrient and endogenous anabolic signals, such as bone-derived osteocalcin, which has recently been identified as a hormone regulating insulin secretion in beta-cells.  We are performing oss-of-function studies of Gprc6a function in vivo and ex vivo to validate and uncover new regulatory networks and pathways whereby different organs coordinate metabolic functions, energy metabolism and body composition through a common receptor that also integrates nutrient and anabolic hormonal signals. We believe that  GPRC6A provides a novel molecular mechanism to link dietary factors, such as amino acids, calcium, and zinc with endogenous factors such as anabolic steroids, and osteocalcin to regulate insulin secretion and beta-cell mass as well as peripheral organ response to insulin.  These paradigm shifting concepts, are also setting the stage for drug development and translational research involving a totally new molecular mechanism involved in regulating energy metabolism.  To this end, working with Oak Ridge National Laboratory (ORNL) and the College of Pharmacy at UTHSC we have developed several lead compounds that act as agonists and antagonists for GPRC6A.

Finally, we have uncovered a new understanding skeletal homeostasis proposes that polycystin 1 (Pkd1, or PC1) and polycystin 2 (Pkd2, or PC2; or TRPP2) form a receptor channel complex that acts as a “physical environment sensor” in cells within the osteoblast lineage to regulate bone mass. This idea is supported by mouse genetic studies showing that selective ablation of Pkd1 and Pkd2 in osteoblasts (Ob) results in osteopenia. Human GWAS studies also link PKD2 with osteoporosis (OP) and with abnormal shape of craniofacial bones in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Osteopenia in Pkd1 conditional knockout mice is due to impaired Ob-mediated bone formation and is associated with increased bone marrow fat, a phenotype resembling senile osteoporosis. The reciprocal relationship between osteoblasts and adipocytes in bone results from effects of Pkd1-deficiency to inhibit Runx2-dependent osteogenesis and stimulate PPARg- dependent bone marrow adipogenesis.  In contrast, Ob-specific deletion of Pkd2 results in impaired Ob functions and osteoporosis in mice, but causes a coordinate suppression of Runx2 and PPARg, leading to impairment of both osteoblast and adipocyte differentiation. We have also found a modulating role for TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1). TAZ is involved in mechanosensing pathways linking “extracellular matrix stiffness” to osteoblastogenesis and adipogenesis through its function as a co-activator for Runx2 and a co-repressor for PPARg activity. Transgenic overexpression of TAZ is a potent inducer of bone mass. TAZ also binds to the PC1-C-terminal tail (PC1-CT) to promote nuclear translocation of TAZ, and TAZ binds and leads to degradation of PC2. Cytoskeletal dynamics are another point of integration of polycystins and TAZ.  Ongoing investigations are attempting to prove that PC1-PC2 complex in osteoblasts/osteocytes controls bone mass by regulating osteogenesis and adipogenesis through regulation of Runx2 and PPARg gene transcription and thatTAZ interactions with polycystins contribute to the reciprocal relationship between osteoblastogenesis and adipogenesis, and is a point of integration between two distinct mechanosensing mechanisms. We are also working with ORNL to explore if structural modeling of PC1 and PC2 interactions can lead to the development of new ways to activate PC1-PC2.

Last Published: Jun 2, 2017