Basic Biology V
$1 161 000
Recommended if funds allow
Arrhythmogenic Cardiomyopathy (AC) is a devastating inherited heart disease associated with a high frequency of arrhythmias and sudden cardiac death in young people, who despite their appearance of health are struck down by this type of heart disease. Early detection is hindered because people carrying the genetic code have highly variable clinical symptoms, making AC and catastrophic cardiac events very hard to predict and avoid. AC is thought to be caused by mistakes in genes essential for holding the mechanical integrity of heart muscle cells together or cell junctions; however, no cures exist. Using the latest technology, we created human stem cell lines from AC patients and show that they display heart disease features that match the patient's heart symptoms as a human model system to better understand the pathophysiologic disease process and enhance early diagnosis of AC. We also uncover a new candidate molecular pathway associated with AC, that could change the way people study and treat AC, which we will molecularly dissect in our AC stem cell lines, to determine the pathway's importance in stem cell derived cardiac cells and as a potential therapeutic target for AC. Knowledge from our studies can be exploited to not only improve management of a heart disease that is not well understood or diagnosed but also clinical outcomes of cardiac stem cell therapies since they rely on achieving proper cell junction integration of cardiac stem cells in the heart for repair.
Statement of Benefit to California:
Heart disease is the leading cause of death and disability within the United States and rates are reported to be higher for Californians when compared to the rest of the nation. This disease places tremendous financial burden on the people and communities of California. We aim to improve heart health and quality of life of Californians by generating human stem cell models generated from people with an especially devastating heart disease that affects young people and results in sudden death, to improve our molecular and medical understanding of how cardiac cells go wrong in the early stages of heart disease. We identified a novel pathway that may be at the "heart" of understanding the disease more clearly and thus, molecularly dissecting this pathway in our diseased stem cell lines, will uncover new therapeutic targets to reverse and intervene with these defects. Our model systems have potential in also being used to diagnose, test an individual's heart cell's response to drug treatment, as well as predict severity and reverse symptoms at an early stage. Knowledge from our studies will be of value to biotechnology companies and academic researchers interested in large scale drug screening strategies to identify more effective compounds to rescue defects and treat Californians with heart disease as well as provide important economic revenue and resources to California, which is stimulated by the development of businesses interested in developing these therapies further.
In this Fundamental Mechanisms proposal, the applicant proposes to use patient-derived induced pluripotent stem cells (iPSCs) to model and explore the pathological basis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited heart disease of heart. Two Aims are proposed to test whether a specific candidate pathway acts as a key contributor to the disease phenotype. In the first Aim, the applicant will compare the activity of this pathway between iPSC-derived cardiac cells from ARVC patients vs. controls. In Specific Aim 2, the applicant will use advanced approaches to determine whether hallmark disease phenotypes can be mechanistically reversed in ARVC cardiac cells. Significance and Innovation - ARVC is a devastating genetic disease that causes sudden cardiac death in young people, but has broad relevance, since it can overlap and model cell junction defects in other heart diseases. - The iPSC lines in this proposal represent a unique tool for probing the underlying mechanisms of ARVC in human cells, for which much is unclear. - The key innovation in this proposal is its focus on the candidate pathway underlying ARVC. If this hypothesis proves correct, these findings could lead to advances in detection and treatment of ARVC. Feasibility and Experimental Design - Reviewers expressed a major concern that the preliminary data at this stage, while suggestive, do not convincingly establish a role for the candidate pathway in the mechanism of ARVC. There is no fall back option in case this central hypothesis is not correct. - Feasibility is weakened by the dependence of Aim 2 on the success of Aim 1. The inclusion of a few additional assays to examine alternative disease mechanisms would be warranted. - The proposal includes a number of novel assays for assessing cell-cell communication and function, and a nice set of alternative approaches to address technical challenges. - The focus on cell junction structure and stability is a strength, but there is little direct attempt to mechanistically link these properties to other reported ARVC phenotypes that may be relevant to clinical manifestations of disease. Principal Investigator (PI) and Research Team - The PI has an impressive funding record and has worked in this area of research for a total of 10 years. While his/her track record of publications as a corresponding author is limited, the preliminary data suggest this PI is on the cusp of greater productivity. - This proposal assembles a terrific team with complementary expertise to assist the PI. Responsiveness to the RFA - The proposed experiments extensively utilize human stem cells and are focused on elucidating molecular mechanisms. As such, they are fully responsive to the RFA.
- Todd C. McDevitt