Funded Research


“Studies of the cell-biology and structural-biology of PACS1/SHMS Syndrome”

Awarded to: Dr Gary Thomas Ph.D., Department of Microbiology and Molecular Genetics, Professor, University of Pittsburgh School of Medicine, and Dr. Angela Gronenborn, Head, Department of Structural Biology, University of Pittsburgh.

Date awarded: November 2018

Summary: Continuation of Cell-biology and Structural biology Research Studies from below on PACS1/SHMS Mutation

Date awarded: November 2017

Summary: We discovered PACS-1 in 1998 and we have shown that this multi-functional protein has key roles in both the cytoplasm and the nucleus. In the cytoplasm, PACS-1 mediates the trafficking of proteases, ion channels and cell surface receptors, and modulates the sensitivity of cells to induction of apoptosis. PACS-1 also shuttles to the nucleus where it interacts with chromatin modifying enzymes that modulate gene expression. We are investigating how the PACS-1 R203W disease mutation, which underlies PACS-1 Syndrome, affects the cellular function and atomic structure of PACS-1. The R203W mutation resides in the critical cargo(furin)-binding region (FBR).

We will therefore rigorously test to what extent the R203W mutation alters binding of a broad panel of important client proteins and to what extent this mutation disturbs the function of the nearby autoregulatory domain, which controls access of client proteins to the FBR. We will leverage cell-based assays that monitor PACS-1-dependent membrane traffic, apoptosis or genome stability to determine which of these pathways may be most profoundly affected by the R203W mutation. Our cell and molecular studies will be complemented by protein structure studies conducted by Dr. Angela Gronenborn’s team (University of Pittsburgh), who is using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to ascertain the atomic structure of PACS-1 R203W. Together, our combined studies will ground our future efforts to identify small molecule compounds that may lead to therapies for treating PACS-1 Syndrome.

“Modeling iPSCs and cortical organoids as a disease model towards finding therapeutics for PACS1 Syndrome"

Awarded to: Dr. Alicia Guemez-Gamboa, PhD, Assistant Professor, Department of Physiology, Feinberg School of Medicine, Northwestern University

Date awarded: May 2019

Summary:Induced pluripotent stem cell (iPSCs) offer the opportunity to work directly with human neurons predisposed to neurological disorders. The recent emergence of human cerebral organoid generation from iPSCs has revolutionized developmental neuroscience research, allowing formation of a complex multicellular structure with the patient’s genetic background. We aim to establish both iPSC-derived neurons and human cerebral organoids as model systems to identify a reliable and reproducible disease phenotype that could serve as a readout in a drug screening platform. These model systems, with its relatively fast production and excellent translatability, will propel PACS1 Syndrome research forward and lay the groundwork for developing new therapeutic approaches and personalized medicine.

“Studies of the Mouse models of PACS1/SHMS Syndrome”

Awarded to: Dr Stacey Rizzo Ph.D., Associate Professor, University of Pittsburgh School of Medicine, Director of University of Pittsburgh’s Preclinical Phenotyping Core Facility for rodents and marmosets.

Date awarded: May 2019

Summary: Study of various Mouse models of PACS1/SHMS Mutation


“Functional Studies on PACS1/SHMS Syndrome in Zebrafish”

Awarded to: Dr Nicholas Katsanis Ph,D., Director, Center for Human Disease Modeling, Duke University