SC BioCRAFT

Project V

RUSSELL (CHIP) NORRIS, PhD Assistant Professor of Cell Biology  Medical University of South CarolinaRole of DCHS1 in Mitral Valve Development

Target Investigator

RUSSELL (CHIP) NORRIS, PhD
Assistant Professor of Cell Biology

Medical University of South Carolina

Email: norrisra@musc.edu
Phone: 843-792-3544

PROGRESS REPORT

Developmental and Biomechanical Mechanisms of Cardiac Valve Tissue Formation

Mitral valve prolapse (MVP) is a major public health burden: One of the most common human diseases, it affects 1 in 40 people worldwide and is the leading indication for surgical repair for mitral regurgitation in the United States. MVP is characterized by systolic billowing of one or both mitral leaflets into the left atrium, impairing leaflet apposition (coaptation) and causing mitral regurgitation. Over time, structural changes in the valve occur due to collagen fragmentation, increased proteoglycan accumulation, aberrant myofibroblast differentiation and hyperplasia (collectively referred to as “myxomatous degeneration”).  Consequentially, the leaflet becomes thicker and mechanically incompetent resulting in mitral regurgitation, frequently requiring surgical intervention to limit secondary defects including heart failure, endocarditis, and sudden cardiac death. It is clear that MVP cannot be categorized as uniformly severe or uniformly benign since patients with MVP have heterogeneous outcomes.  Nearly half of the individuals diagnosed with MVP will require some aspect of intervention (surgery, medical management, etc.) and ~18% are considered high-risk with increased mortality and cardiovascular morbidity. Even though MVP has been classically viewed as an adult-onset disorder, studies of affected families indicate childhood manifestation, suggesting genetic abnormalities expressed during development become exacerbated over a lifetime. Uncovering how MVP genes regulate downstream signaling cascades will provide key mechanistic insights into how cell biology impacts normal valve mechanobiology during development and aging. The discovery and mechanistic understanding of genes causal to MVP will uncover disease etiologies and identify targeted therapeutics beneficial for patients

Etiology and Treatment of MVP: MVP can be a syndromic or non-syndromic disease.  “Syndromic MVP” refers to mitral valve prolapse in the context of other structural multisystem phenotypes (e.g. Marfan Syndrome). Gene mutations that cause some rare MVP-associated connective tissue syndromes and X-linked myxomatous valvular dystrophy are known. However, the genetic underpinnings of the more common non-syndromic form of MVP has remained elusive; consequently, the etiology of the disease remains poorly understood. In collaboration with members of our previously funded Leducq Network we have identified mutations in the DCHS1 cadherin gene that segregates with mitral valve prolapse in multiple families. This is the first discovery of a gene that causes the common form of MVP in humans and is a critical step towards understanding disease etiology, pathogenesis, as well as provide new indications for remedial therapies.  As curative non-surgical treatments for MVP are not currently available, these studies have potential to revolutionize medical management of the disease with outcomes expected to decrease surgical intervention, morbidity and mortality.

Our central hypothesis is that linear arrays of cells established through the activity of cell polarity genes (e.g. DCHS1) engender matrix alignment during valve development.  We propose that this establishment of proper cell-ECM architecture engenders life-long valvular mechanical stability critical for proper function. This represents a novel paradigm by which valve morphogenesis proceeds and answering the question of how cell polarity engenders tissue shape and biomechanical stability is the basis of this proposal.

To test this hypothesis, molecular, cellular, and bioengineering approaches will be utilized to define how disruption of the cell polarity gene, DCHS1 perturbs normal development resulting in mitral valve prolapse in humans. Collaborations with the COBRE core facilities (Bioengineering and Bioimaging Core and Cell, Tissue, and Molecular Analysis Core) will provide unique opportunities to answer biophysical questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the-art biological and genetic approaches.

Specific Aims are:

Aim1: To test the hypothesis that Dchs1 functions during development to regulate asymmetric membrane distribution of cell polarity proteins on valve progenitor cells and to confirm the possible relationship between Dchs1 and cellular positional information, alignment, and matrix organization into histological zones.

Aim2: To test the hypothesis that effects of Dchs1 are mediated by changes in the directed, polarized growth of cytoskeletal microtubules.

Highlights / Progress / Papers:

Progress has been made on both of the proposed aims and has been included in 3 manuscripts that are currently in press, 3 that are under review/revision, and 3 that are pending submission.  Success of these studies is highlighted in both the impact of the manuscripts (Nature Reviews, Nature, and Nature Genetics) as well as scores received from recent grant applications, speaking invitations, and plenary talks at various national and international meetings as detailed below.

Grants:

  • PI: RO1 (A0) Scored 19%, Revision Submitted November 5th, 2014
  • PI: AHA (A0) (1.8 Impact Score, 40%), Revision Submitted Jan 5th, 2015
  • Leducq Proposal (Norris: Co-I): Markwald (US-PI) /Kohl (Eu-PI)—pre-application approved and in top 14 (will fund 5-6) after submission of full proposal (Feb. 8, 2015)
  • New RO1 for June on Cilia and Valve Disease and its integration with mechanical stimuli
  • Promising Co-I grants:
    • RO1 (funded as R56 mechanism)--MUSC
    • RO1 (Received a 10%)--MUSC
    • RO1 (Received a 10%)—Collaboration with MGH/Harvard

Speaking Invitations in 2014/2015:

  • Yale (Pediatric Grand Rounds), Pitt, UNC Chapel Hill, Imperial College (London), Virginia Tech, MUSC, USC, Harvard/MGH

Plenary Talks and Posters in 2014/2015:

  • AHA (poster), Weinstein (poster and talk), Heart Valve Summit (talk), COBRE meeting in DC (poster), Keystone Meeting (talk), Heart Valve Society in Monaco (Talk).