RASopathy Disorders
Dr. Kontaridis is invested in the study of congenital heart disease, heart failure and metabolic cardiomyopathies, including heart failure with preserved ejection fraction (HFpEF), dedicating her research efforts to unraveling the mechanisms causal to these diseases. Her research is not just about discovering new knowledge but is also geared towards translating these findings into effective treatments that could significantly improve patient outcomes. Currently, she is focused on studying the functions of both the SH2 domain-containing protein tyrosine phosphatase (SHP2), the Protein tyrosine phosphatase 1B (PTP1B), and the phosphoglycolate phosphatase (PGP) in heart development and disease.
Phosphatase dependent and independent functions of SHP2
Dr. Kontaridis' research on SHP2 has unveiled novel functional dimensions for this phosphatase. Notably, Dr. Kontaridis was the first to uncover that mutations associated with NSML are loss-of-function and render SHP2 catalytically inactive, whereas mutations in NS are gain-of-function and lead to increased activity of SHP2. This paradigm-shifting revelation has transformed the understanding of phosphatase function within cellular signaling networks, advocating for a mutational-based approach in distinguishing RASopathies as well as created an opportunity to consider the role of these enzymes in phosphatase-dependent versus independent capacities in mediating downstream molecular signaling effects.
Lupus
Systemic lupus erythematosus (SLE) is a devastating autoimmune disorder characterized by widespread inflammation. However, the molecular mechanisms causal to SLE, as well as the identification of targeted therapies, remain largely unknown. Dr. Kontaridis is investigating the potential mechanisms associated with development of SLE. Her findings reveal a compelling link between heightened SHP2 activity and SLE; elevated SHP2 activity leads to increased proliferation of cytotoxic T cells and exacerbated lupus pathogenicity. In a groundbreaking endeavor, she explored the therapeutic potential of a novel SHP2 inhibitor in alleviating SLE symptoms. Remarkably, her experimental results demonstrated that inhibition of SHP2 not only extended lifespan but also mitigated fibrosis, reduced tissue inflammation, and diminished skin lesions in SLE. These compelling insights underscore the pivotal role of SHP2 in driving SLE progression and suggest that targeting SHP2 could offer a promising avenue for the development of innovative therapies to combat this debilitating autoimmune disease. In addition, the lab is working to delineate the mechanisms by which SHP2 mediates the activation of macrophage to induce onset of SLE. Moreover, since SLE is a multifactorial disease, she is also actively working to understand the precise genetic and molecular mechanisms associated with myocarditis and lupus nephritis (LN), two devastating effects of SLE, to identify specific and targeted therapies to treat patients with these aspects of this disorder.
Protein Tyrosine Phosphatases (PTPs)
Dr. Kontaridis is invested in the study of congenital heart disease, heart failure and metabolic cardiomyopathies, including heart failure with preserved ejection fraction (HFpEF), dedicating her research efforts to unraveling the mechanisms causal to these diseases. Her research is not just about discovering new knowledge but is also geared towards translating these findings into effective treatments that could significantly improve patient outcomes. Currently, she is focused on studying the functions of both the SH2 domain-containing protein tyrosine phosphatase (SHP2), the Protein tyrosine phosphatase 1B (PTP1B), and the phosphoglycolate phosphatase (PGP) in heart development and disease.
Autism
Autism affects one out of every 36 children. Dr. Kontaridis’ lab is focused on understanding the genetics of autism. She is evaluating the genetic sequences of all family members with generational cases of autism to try to identify novel familial causes of this disorder. Already, her work has identified a link between congenital heart disease and autism and is working to identify therapeutic targets for intervention early. In addition, she is working to assess phenotype:genotype correlations for incidence of autism in the upstate NY area. In partnership with several autism foundations, her lab is working to conduct a study to identify a link between genetic, environmental, and socioeconomic determinants to the development of autism.
Diabetes/Obesity
Characterized by diastolic dysfunction, myocardial stiffness, and preserved systolic function, HFpEF represents a significant and increasing portion of heart failure cases. Despite its prevalence, the molecular mechanisms underlying HFpEF remain poorly understood, and effective therapeutic targets are lacking. The Kontaridis lab is interested in a novel phosphatase that may be involved in the regulation of cardiac metabolism. The lab is focused on determining a role for phosphatases in HFpEF. Specifically, PTP1B is a critical protein tyrosine phosphatase involved in a variety of cellular signaling pathways, including metabolism, inflammation, and cardiovascular function. Importantly, Dr. Kontaridis’ lab has shown that PTP1B plays a crucial role in high fat diet (HFD)-induced cardiac hypertrophy and fibrosis, key features of HFpEF. The current work in the lab, therefore, is focused on whether PTP1B is a nodal enzyme required for the regulation of HFpEF through aberrant regulation of downstream signaling. In addition to PTP1B, the lab is also interested in assessing the function of another novel phosphatase, PGP, in the heart and in metabolic signaling.
Channelopathies
The Kontaridis lab is also working to delineate the molecular and cellular underpinnings of genetically induced cardiac channelopathies, including short QT (SQT), long QT (LQT), and Brugada syndromes, rare congenital heart disorders that cause life-threatening cardiac arrhythmias. Her studies encompass studying novel gene mutations that gives rise to disparate arrhythmias, including in the TRPM4, calcium, potassium, sodium and/or ryanodine receptor channels.
Heart Failure, Inflammation, and Fibrosis
The Kontaridis lab is also deciphering the mechanisms that affect cardiac fibrosis, induce heart failure and/or cardiometabolic disorders. Dr. Kontaridis discovered that the Rho GTPase RhoA, an enzyme regulated in part by SHP2, is involved in transitioning compensatory cardiac hypertrophy to heart failure. Moreover, it is involved in fibrosis, making RhoA and its downstream effectors attractive targets for therapeutic approaches in treating cardiac disease. Our projects on RhoA involve elucidating signaling pathways involved in fibrosis, inflammation, and in the onset of end-stage heart failure.
Lab Members
Chase Kessinger, Ph.D.
Chase Kessinger, Ph.D.
