Candidate: Dr. Clines obtained his M.D. and Ph.D. degrees as a Medical Scientist Training Program student at the University of Texas Southwestern Medical Center in 1991. In his graduate studies, he developed positional cloning techniques to rapidly identify human genes responsible for skeletal dysplasias. Dr. Clines completed an internal medicine residency at Duke University Medical Center in 2001. This was followed by an endocrinology fellowship at the University of Virginia in the laboratory of Dr. Theresa Guise, studying molecular mechanisms of metastatic bone disease and the role of endothelin-1 (ET-1). He joined the faculty of the University of Virginia Health System in July, 2005 with the goal of becoming an independent academic physician-scientist. Dr. Clines will learn new laboratory techniques in cancer biology and participate in coursework and conferences. Environment: Dr. Clines'co-mentor, Dr. Theresa Guise, is a world leader in research on the molecular mechanisms of skeletal metastasis and will instruct him in the use of mouse bone metastasis models. His other co-mentor, Dr. John Chirgwin, will advise him on the proper application of molecular biology techniques. Drs. Henry Kronenberg and Barry Gumbiner will give outstanding guidance on the role of Wnt signaling in bone development and metastasis. Dr. Richard Santen will assist Dr. Clines in the design and interpretation of cellular signaling experiments. The University of Virginia Cancer Center, headed by Dr. Michael Weber, and Division of Endocrinology provide extensive support for academic training and research in cancer and bone at basic, preclinical and clinical levels. Research: Cancer cells that secrete ET-1 cause osteoblastic bone metastases by activation of osteoblasts. Dr. Clines has identified major factors regulated by ET-1 in osteoblasts: dickkopf homolog 1 (Dkk1) and snail homolog 1 (Snai1). He theorizes that these two factors stimulate osteoblasts by activating canonical Wnt signaling and driving the formation of osteoblastic bone metastases.
Three aims are proposed: 1) determine the physiological significance of Dkk1 in osteoblastic bone metastasis;2) determine the role of Snai1 in regulating osteoblast canonical Wnt signaling;and 3) determine how ET-1 regulates the expression of Dkk1 and Snai1. Relevance: Bone metastases cause significant and protracted pain and disability as the result of a vicious cycle -- invading cancer cells produce factors that activate bone cells, which produce additional factors that in turn stimulate the cancer cells. Dr. Clines'research will investigate the molecular interactions of cancer and bone cells and develop preclinical models to test therapeutic interventions of bone metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08CA118428-05
Application #
8054048
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2006-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$124,492
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Clines, Katrina L; Clines, Gregory A (2018) DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis. Transl Oncol 11:873-882
Grunda, Jessica M; Wang, Dezhi; Clines, Gregory A (2013) Development and characterization of murine models of medulloblastoma extraneural growth in bone. Clin Exp Metastasis 30:769-79
Clines, Gregory A; Mohammad, Khalid S; Grunda, Jessica M et al. (2011) Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. J Bone Miner Res 26:2523-36
Clines, Gregory A (2011) Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes 18:339-46
Clines, Gregory A (2010) Prospects for osteoprogenitor stem cells in fracture repair and osteoporosis. Curr Opin Organ Transplant 15:73-8
Clines, Gregory A; Guise, Theresa A (2008) Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 10:e7
Clines, Gregory A; Mohammad, Khalid S; Bao, Yongde et al. (2007) Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol 21:486-98
Brown, Sue A; Clines, Gregory A; Guise, Theresa A (2007) Local effects of malignancy on bone. Curr Opin Endocrinol Diabetes Obes 14:436-41