Patrick Smits PhD

LIke ThisLIke ThisLIke ThisLIke ThisLIke This

Dr. Smits' research interests focus on an understudied question in the skeletal field: how do chondrocytes and osteoblasts deal with the high demand for production and secretion of proteins needed to maintain a functional extracellular matrix? This is an important question to ask, because its answer would help to clarify the properties of bone and cartilage. The long-term goal of Dr. Smits' research is to identify the mechanisms and pathways involved in intracellular trafficking of matrix proteins by chondrocytes and osteoblasts during skeletal development, homeostasis and disease. He receives his PhD from University of Antwerp, Belgium and trained with Dr. B. de Crombrugghe and Dr. V. Lefebvre, two leaders in the skeletal field.

 

 

Delineating protein trafficking pathways using heritable disorders of bone and cartilage

The process responsible for transport of proteins from their synthesis in the ER, to and through the Golgi apparatus towards their correct deposition in or outside the cell is called membrane/or protein trafficking. Recently I have identified that the rare human neonatal lethal skeletal dysplasia Achondrogenesis type 1A is caused by mutations in the TRIP11 gene. TRIP11 encodes for the membrane trafficking protein GMAP210, a member of the Golgin protein family. Golgins are involved in the tethering of intracellular transport vesicles to their destination compartment and in maintenance of the Golgi structure. The most striking feature of ACG1A is the accumulation of proteins in the ER cisternae of chondrocytes and osteoblasts. Furthermore, several cell types, including chondrocytes and osteoblasts, exhibit abnormal Golgi architecture in Trip11-null mice. Studies of other membrane trafficking diseases, such as Hermansky-Pudlak and Griscelli syndrome, have shown that mutations in several different genes can cause similar phenotypes. Functional studies of these genes subsequently led to the identification of a molecular pathway. The same principle would apply to the membrane trafficking pathway in which GMAP210 functions. Mutations in proteins that functionally interact with GMAP210 could therefore result in phenotypes similar to ACG1A. The goal of this proposal is to identify these proteins and determine whether their depletion affects skeletal development. GMAP210 interacting proteins will be identified using both a co-immunoprecipation approach and a high throughput yeast 2-hybrid screen using the human ORFeome (Dana Farber Cancer Institute). To quickly determine whether mutations in identified proteins result in skeletal dysplasias, I will determine the effects of their depletion on skeletal development through morpholino mediated knockdown of their zebrafish orthologues in vivo. I will also continue to perform DNA-based mutation detection in patients in which ACG1A is suspected, in order to identify patients whose disease is not caused by mutations in TRIP11. These patients will subsequently be analyzed for mutations in the genes of identified GMAP210 interacting proteins. Successful completion of the proposed experiments will elucidate the molecular pathway(s) in which GMAP210 functions and it will lead to the identification of new candidate genes for ACG1A related diseases.

Request an Appointment

If this is a medical emergency, please dial 9-1-1. This form should not be used in an emergency.

Patient Information
Date of Birth:
Contact Information
Appointment Details
Send RequestIf you do not see the specialty you are looking for, please call us at: 617-355-6000.International visitors should call International Health Services at +1-617-355-5209.
Please complete all required fieldsThis department is currently not accepting appointment requests onlineThis department is currently not accepting appointment requests online

Thank you.

Your request has been successfully submitted

You will be contacted within 1 business day.

If you have questions or would like more information, please call:

617-355-6000 +1-617-355-6000
close
Find a Doctor
Search by Clinician's Last Name or Specialty:
Select by Location:
Search by First Letter of Clinician's Last Name: *ABCDEFGHIJKLMNOPQRSTUVWXYZ
More optionsSearch
Condition & Treatments
Search for a Condition or Treatment:
Show Items Starting With: *ABCDEFGHIJKLMNOPQRSTUVWXYZ
View allSearch
Visitor Information
The future of pediatrics will be forged by thinking differently, breaking paradigms and joining together in a shared vision of tackling the toughest challenges before us.”
- Sandra L. Fenwick, President and CEO
Close