Role of PARylation on cardiovascular disease in progeroid syndromes – PAR-AGING

Progeroid syndromes (PSs) are rare genetic disorders mimicking clinical and molecular features of aging. Among all of the clinical features associated with premature aging, the cardiovascular disease is the cause of death in almost all patients. Despite its great importance, investigation of the arterial pathology has been extremely limited mainly due to the low incidence of PSs.
Vascular smooth muscle cells (SMCs) are important in maintaining aortic integrity. It is known that the abundance and functionality of SMCs decline with aging in animal models of progeroid syndromes. Recent studies identifies progerin-induced SMCs death as a major factor triggering atherosclerosis and premature death in progeria. However, the mechanisms of how ‘‘progerin’’ leads to massive SMCs loss are largely unknown.
The role of NAD+ as co-substrate has emerged as an exciting target that can impact the cardiovascular system both directly and indirectly. NAD+ is an important co-substrate for different classes of enzymes, among which the poly(ADP-ribose) polymerases (PARPs). NAD+ is consumed by PARP to catalyze the transfer of ADP-ribose moieties from NAD+ to protein acceptors, generating Poly(ADP-Ribose) (PAR) chains (i.e. PARylation). While it remains unclear how the activation of PARylation signaling in the SMCs leads to cardiovascular dysfunction, our preliminary studies clearly show that abnormal PARylation is correlated with the pathophysiology of progeroid syndromes. However, the understanding of molecular and cellular mechanisms underlying the modulation of PARylation signaling in the SMCs remains to be uncovered.
Using patients’ primary fibroblasts, SMCs derived from human iPSC, primary mouse SMCs as well as aorta from mouse models of progeroid syndromes and WT mice, the project we propose aims to precisely characterize the molecular mechanisms leading to loss of SMCs by analyzing PARylation in PSs (NAD metabolome analysis and generation of proteomic maps of PARylation targets: PARylome) and its role on genomic stability (DNA repair, DNA double-strand break) as well as SMCs calcification.
We next aim to perform a drug discovery program on iPSCs lines, by studying the impact of effective compounds already identified (Olaparib, PARP inhibitor) or by high-throughput drug screening for in vivo pharmacological intervention. The effectiveness of identified drug candidates will be evaluated in progerid mice models (LmnaG609G/G609G, Zmpste24 null). We will examine if the disease phenotypes are ameliorated after treatment and evaluate the vascular calcification as well as SMCs functions.
A large number of patients’ cohorts have been collected by the coordinator, constituting a European reference center for diagnosis and research on patients affected with PSs and related diseases. Coordinator provided the scientific community with major achievements in the field of PSs at the clinical, diagnostics and research levels. Previous work has allowed the coordinator to discover the genetic cause of progeria. Partner 1 has an outstanding experience in high-throughput drug screening identifying a novel class of farnesylation inhibitors involved in PSs. Partner 2 delineated essential biological information in regards to the pathological processes involved in several devastating syndromes of accelerated aging. Furthermore, coordinator and partners 2 already have a long-lasting and fruitful collaboration in preclinical and clinical research on PSs, allowing to set-up a Phase II clinical trial for children with progeria.
Our project covers basic cellular and molecular biology up to translational research to uncover pharmacological targets, and to test novel therapeutic compounds in human cells and animal models. Furthermore, this project has a great potential of success due to the skills of the groups involved, with major potential spin-offs in terms of insights into cardiovascular involvement in progeroid syndromes as well as physiological aging.