Browsing by Author "Krishnan, Subha"

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    Differential role of PI-3Kinase p85 (α & β) regulatory subunits in mast cell development
    (2011-08) Krishnan, Subha; Kapur, Reuben; Wek, Ronald C.; Quilliam, Lawrence; Mooney, Sean D.
    Stem cell factor (SCF) mediated c-Kit signaling, and downstream activation of Phosphatidylinositol-3 Kinase (PI-3K) is critical for multiple biological effects mediated by mast cells. Mast cells express multiple regulatory subunits of PI-3Kinase, including p85α, p85β, p50α and p55α. In the present study, we have examined the relationship between p85α and p85β subunit in mast cell development and show that loss of p85α in mast cell progenitors impairs their growth, maturation and survival whereas loss of p85β enhances this process. To further delineate the mechanism (s) by which p85α provides specificity to mast cell biology, we compared the amino acid sequences between p85α and p85β subunits. The two isoforms share significant structural homology in the two SH2 domains, but show significant differences in the N-terminal SH3 domain as well as the BCR homology domain. To determine whether the c-Kit induced reduction in growth of mast cells is contributed via the N-terminal SH3 or the BCR homology domain, we cloned and expressed the shorter splice variant p50α, and various truncated mutant versions of p85α in p85α deficient mast cells. We demonstrate both invitro and invivo that while the SH3 and the BH domains of p85 are dispensable for mast cell maturation; they are essential for normal growth and survival. In contrary to existing dogma on redundant functional role of PI-3K regulatory subunits, this study proves that p85α and p85β regulatory subunits of PI-3K have unique roles in mast cell development. We prove that p85α deficiency impairs the expression of multiple growth, survival and maturation related genes whereas p85β deficiency inhibits c-Kit receptor internalization and degradation. This novel finding on negative role of p85β in mast cell development has significant clinical implication, as this knowledge could be used to develop treatments for mast-cell-associated leukemia and mastocytosis.
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    Genomics of Osteoporosis
    (2004-08) Krishnan, Subha; Econs, Michael J.
    Osteoporosis is the most common bone disease in United States and developed countries and a major public health threat for an estimated 44 million Americans. It is characterized by low bone mineral density and micro architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture, especially of hip, spine and wrist. Osteoporosis is multifactorial disease influenced by large number of environmental and genetic factors. Though a number of FDA approved drugs are available for treating this complex disease, a medication, which could specifically and effectively reverse symptoms of it is lackin. As the initial step for approaching disease treatment my current research focuses on locatin candidate genes on linkage regions for BMD on human chromosomes, which potentially can be used for developing novel targets and strategies for therapeutic interventions. We will also define the mouse homologs in the syntenic regions as basis for future studies involving animal models of disturbed BMD. An automated interface which will give information on human - mouse synteny between human marker intervals of interest was developed which will expedite future synteny studies.