Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions
NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
About This Grant
Project Summary/Abstract This proposal describes a 5-year plan for Dr. Portales-Castillo to become an independent investigator with expertise in parathyroid hormone /parathyroid hormone related peptide receptor (PTH1R) signaling in patients with skeletal dysplasias. Dr. Portales completed his clinical nephrology training at the Massachusetts General Hospital (MGH). During his time as a clinical fellow and following his interest in renal osteodystrophy, he learned basic research at the Endocrine Unit in the Laboratories of Drs Jüppner and Gardella, leaders in PTH1R research. Dr. Portales work at MGH included the functional characterization of homozygous PTH1R mutants found in patients with Eiken syndrome. Patients with Eiken syndrome have delayed ossification, i.e gain of function effects on PTHrP pathways at the growth plate, but on the other hand, exhibit resistance to PTH actions in proximal renal tubule (PT). Thus, Eiken syndrome exemplifies a paradox in PTH1R signaling: How can the same receptor lead to gain-of-function effects for the function of one of the ligands (PTHrP) but loss-of-function for the other ligand (PTH)? By performing detailed in vitro analyses, Dr. Portales found that three PTH1R mutants found in patients with Eiken syndrome fail to desensitize when treated with PTHrP but not with PTH. Of special interest for this project, is the PTH1R mutant R485X. The PTH1R-R485X mutation introduces a premature stop codon that truncates the receptor C- , a key molecule for receptor desensitization. Derived from the insights gained from the in vitro findings, a novel humanized mouse model of Eiken syndrome was generated. In his role, as an Assistant Professor at Washington University of St. Louis, Dr. work revealed that delayed ossification in the novel humanized Eiken mice is caused by enhanced response to PTHrP in vivo and that like humans, Eiken mice exhibit resistance to PTH calcemic actions . In separate experiments, Dr. Portales also observed that the mammary fat pad (MFP) of mice with Eiken syndrome is smaller due to enhanced PTHrP actions in adipose tissue. The overall hypothesis of this proposal is that the PTH1R C-tail interactions are required to restrain PTHrP responses at the growth plate and adipose tissue but on the other hand promote PTH response in the PT. To test this hypothesis, the proposal has 3 aims: Aim 1 Aim 2: Aim 3: . Trough the work over the next 5 years with his mentorship team comprising of leaders in bone (Drs. Civitelli, Nickolas, Jüppner and Gardella), adipose tissue (Dr. Brian Finck) and PT (Dr. Humphreys) fields, Dr. Portales can leverage this K08 award to become and independent investigator with expertise in PTH1R signaling.
Grant Summary
Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions is a NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases grant providing up to $192K for university, nonprofit, healthcare org. Applications are due 2031-01-31 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $192K
2031-01-31
- 1Confirm your organization is eligible for Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases before the deadline.
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Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions: Frequently Asked Questions
Who is eligible for the Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions?
Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions is offered by NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions provide?
Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions provides up to $192K per award from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions deadline?
Applications for Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions are due 2031-01-31 (open). Because deadlines can change, verify the date with the funder, NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions?
To apply for Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases.