My research focuses on parathyroid function and disease. As a physician-scientist, I have the great fortune that my research spans the basic, translational, and clinical realms of the disease.
Our basic research focuses on the parathyroid-specific master regulator GCM2 and its mode of action as well as the alpha subunit of the G protein G11. Our translational projects include research on a long-acting PTH and its use in hypoparathyroidism. Our clinical studies focus on the long-term consequences of hypoparathyroidism and its current treatment, and on using PTH(1-84) for this disease.
Mode of Action of GCM2, the essential parathyroid transcription factor
GCM2 is a transcription factor that is essential for the development of parathyroid glands. Our previous work showed that heterozygous mutations in GCM2 cause a familial form of hypoparathyroidism. We are currently investigating target genes and binding partners for this transcription factor, as well as the role of the continued expression of this transcription factor in adult parathyroid tissue.
Mutations in the alpha subunit of G11 and hypoparathyroidism
We found that heterozygous mutations in the alpha subunit of G11 can cause primary hypoparathyrodism; recent functional studies have shown that this mutant G protein fails to normally transmit the signal of the calcium-sensing receptor. Our research is aiming to unravel the function of G11 in the parathyroid glands.
Long-acting PTH for hypoparathyroidism
We have developed a novel class of long-acting PTH analogs that were identified because of their unique mode of action at the PTH/PTHrP receptor (PTHR1). When injected into animals, including rats with induced hypoparathyroidism, these analogs mediate calcemic responses that can last 24 to 48 hours. We are pursuing the development of a long-acting PTH via a collaboration with the NIH NCATS/TRND program.
Dr. Mannstadt is the site-PI for the following clinical trials:
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