? ? The proposed plan for the K22 award is one year of the scholar phase and four years of the faculty development phase. The scholar phase will be spent pursuing advanced postdoctoral training in the laboratory of Dr. Andrew Arnold at the University of Connecticut Health Center. This phase of mentored training is designed to allow me to concentrate my efforts on research and career development. During this period, we will investigate the molecular mechanisms of hyperparathyroidism (HPT). A hallmark of parathyroid adenomas is their loss of calcium sensitivity--an apparent resetting of the 'setpoint' mechanism that normally tightly couples PTH secretion with ambient calcium levels. In these tumors, the processes of hormonal dysregulation and proliferation seem to be inexorably linked. However, the mechanisms that underlie these crucial and consistent links are not yet known. We have recently developed a mouse model of primary HPT. In this model, we have established that primary deregulation of cyclin D1 causes a secondary disturbance in parathyroid proliferation and in the calcium-PTH secretory relationship. Examination of the contribution of cyclin D1 to deregulation of setpoint control will elucidate the critical links between proliferation and functional abnormalities in parathyroid neoplasia. In our mouse model of primary HPT, cyclin D1 deregulation causes hypercellularity and enlargement of the parathyroid glands. However, it has not been established whether these glandular enlargements represent polyclonal proliferations or clonal expansions. Examination of the clonal nature of these lesions will shed light on the oncogenic mechanism of cyclin D1 and will form the basis for future studies on the genetic regulation of parathyroid tumorigenesis in this animal model of HPT. Research proposed for the faculty phase will study the molecular mechanisms of oral neoplastic progression. These studies will exploit a recently developed mouse model of upper aero-digestive cancer. In this model, tissue-specific dysregulation of cyclin D1 causes epithelial dysplasias in the tongue, esophagus and forestomach. This model will be used to study the interaction of cyclin D1 overexpression with chemical carcinogens in the development of oral squamous cell carcinoma, and the molecular and genetic events that occur during the progression of cyclin D1-induced dysplasias. These studies will elucidate our understanding of cyclin D1's role in oral premalignancy and malignancy and the molecular events in the multistep oral carcinogenic process.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Career Transition Award (K22)
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NIDCR Special Grants Review Committee (DSR)
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Hardwick, Kevin S
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University of Connecticut
Other Basic Sciences
Schools of Medicine
United States
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Mallya, Sanjay M; Wu, H Irene; Saria, Elizabeth A et al. (2010) Tissue-specific regulatory regions of the PTH gene localized by novel chromosome 11 rearrangement breakpoints in a parathyroid adenoma. J Bone Miner Res 25:2606-12
Woods, Michael; Pant, Rima; Mallya, Sanjay M (2010) Cyclin D1 and cyclin D-dependent kinases enhance oral keratinocyte proliferation but do not block keratinocyte differentiation. Int J Oncol 37:1471-5
Patel, Milan M; Wilkey, Jonathan F; Abdelsayed, Rafik et al. (2010) Analysis of GNAS mutations in cemento-ossifying fibromas and cemento-osseous dysplasias of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:739-43
Wilkey, Jonathan F; Buchberger, Glenn; Saucier, Kirsten et al. (2009) Cyclin D1 overexpression increases susceptibility to 4-nitroquinoline-1-oxide-induced dysplasia and neoplasia in murine squamous oral epithelium. Mol Carcinog 48:853-61
Mallya, Sanjay M; Buchberger, Glenn K; Arnold, Andrew (2007) Effects of anesthetic agents on serum parathyroid hormone and calcium concentrations in mice. Vet Anaesth Analg 34:403-7
Mallya, Sanjay M; Gallagher, James J; Wild, Yvette K et al. (2005) Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. Mol Endocrinol 19:2603-9
Mallya, Sanjay M; Gallagher, James J; Arnold, Andrew (2003) Analysis of microsatellite instability in sporadic parathyroid adenomas. J Clin Endocrinol Metab 88:1248-51