Hereditary Hemorrhagic Telangiectasia: Vascular Biology - and Pathophysiology - Future Directions

Hereditary Hemorrhagic Telangiectasia: Vascular Biology
and Pathophysiology

Future Directions

• Transforming Growth Factor-? pathway
• Vascular Biology
• Endothelial Biology
• Organ Pathophysiology

On the second day of the meeting, each attendee participated in a workshop subgroup focused on one of the following areas: the transforming growth factor-? pathway, vascular biology, endothelial biology, and organ pathophysiology. Each of the subgroups was asked to focus on three questions:

What are the most promising opportunities for HHT research in this area?
What are the current major obstacles to this area of research?
What are the best ways to advance this area of research?

The discussions from these workshops were then shared with, and refined by, the larger group, resulting in the following summary of future directions for HHT research.

Transforming Growth Factor-? pathway

What are the most promising opportunities for HHT research in this area?

• Fleshing out the ALK1, endoglin and Smad4 signaling pathways
  • Unresolved questions....
    • What is the ligand(s)?
    • What is the cognate type II receptor?
    • What are the most relevant downstream targets?
    • Are there relevant Smad-independent pathways and factors involved in disease pathogenesis?
    • Relevance of the activation/resolution paradigm in HHT signaling and pathogenesis
• In vitro signaling with new ligands
• Validation of novel findings using in vivo models
• Identification of downstream targets using microarray and/or proteomic approaches both in vitro and in vivo
• All in vivo experiments of signaling require better imaging modalities for animals
• In vivo experiments would benefit from more robust, highly penetrant animal models
• Regulation of ALK1, endoglin expression levels
• Physiological and other means of up-regulating endoglin and ALK1 expression levels (validate in vitro data using in vivo models)
• Interaction of ALK1, endoglin and Smad pathways with other signaling pathways, eg) VEGF, apoptosis, others
• Identification of modifiers of signaling and downstream effect (in vitro analyses and in vivo)
• Would include cell biological approaches and also in vivo validation in animal models
• Chemical Genomics/Proteomics
  • Chemical genomics: need for small molecule inhibitors of specific HHT related targets including ALK1, endoglin, Smad4
  • Above requires development of in vitro and in vivo assays relevant to signaling pathways
  • Phosphoprotein profile of relevant animal models
• Answering such questions in signaling as:
  • What is the ligand relevant to HHT pathogenesis?
  • Is the "phases of angiogenesis" paradigm (activation/resolution) still viable in our understanding of HHT? How should it be modified?
  • What are the downstream targets of ALK1/endoglin signaling that are relevant to HHT pathogenesis?
  • What is the role of Smad-independent pathways/factors in HHT pathogenesis? (eNOS, cytoskeletal scaffold proteins, others)
  • How can we best use in vivo models to validate the in vitro data?

What are the best ways to advance this area of research?

Shared tools and resources

• Mouse:
  • floxed alleles of HHT target genes
  • EC and SMC cre-transgenic lines
• Human/Patient
  • Plasma from genetically-defined HHT patient cohort, levels of cytokines, etc.
  • Collaborative grants combining signaling studies with cellular and in vivo models including clinical studies of patients to integrate signaling studies with big picture

 

Vascular Biology

What are the most promising opportunities for HHT research in this area?

• Connecting HHT to other vascular diseases to understand vascular biology
• Links with cancer/ coronary artery disease? Higher/lower incidence - what does it tell us about mechanisms?
• Focal nature of the disease - underlying mechanisms (differential organ involvement -different vascular beds)
• Arteroigenesis

What are the current major obstacles to this area of research?

• Money
• How does one sell HHT as a model to basic researchers?
• Lack of "joined up" thinking between basic science, applied, and clinical (possibly as a result of funding constraints forcing investigators to make a choice between these areas)

What are the best ways to advance this area of research?

• Shared tools or resources
  • Natural history database (PET, coronary vessel disease, etc.)
  • Resource center(s) (HHT lesion skin punches, peripheral monocytes, HUVECs, clinical phenotyping, molecular phenotyping)
• Support for translational research (RFA)
• HHT resources, so that HHT can be a research topic in its own right
• Funding of vascular biology research
• Mouse studies using pathophysiological stresses
• RFAs that promote integrated research
• PPG on vasculopathy - crossing institutions

Endothelial Biology

What are the most promising opportunities for HHT research in this area?

• Are HHT lesions pre-determined or are lesions a manifestation of defects in vascular repair?
  • 129 mice - more severe ? lesions at early age (progression?)
  • C57 mice - mild phenotype ? no lesions
    • Possible opportunity to address the question ? does environmental stress (injury) induce HHT lesions in C57
• What do the patients tell us ? do at least some lesions develop in response to injury/repair??
  • Telangiectasia on finger tips of volley ball player
  • Lesions in GI tract - located in areas food trauma
  • Lesions at the border of skin flaps and area of UV exposure (e.g., lower lip)
• Understanding interacting pathways
  • eNOS
  • Estrogen / progesterone
  • Matrix / integrins
  • Other growth factors (VEGF)
  • Other...

What are the current major obstacles/needed resources in this area of research?

Appropriate EC models

• Human vs. mouse models
  • WT, Eng/Alk mutations
• Vascular bed specific
  • Human sources: GI, Skin, nasal, liver (lung less available)
• Vascular region (artery/vein; arteriole; cap...)
• Circular progenitors (markers, early or late outgrowth EPCs)
  • Opportunity for standardization ? cell blanks?
• Assays
  • Standard (prolif, apoptosis, migration, tube formation ...)
  • Shear stress, stretch, remodeling
  • 3-D assays
  • Co-culture
  • Ex vivo - e.g., yolk sac
  • In vivo - Langille model (unilateral carotid ligation)
  • High throughput assays

What are the best ways to advance this area of research?

• Good Clinician to investigator communication and coordination
• NIH Program Announcement
• Young Investigators
• "Spin"

Organ Pathophysiology

What are the most promising opportunities for HHT research in this area?

• Study human phenotype
  • Better characterization
  • Correlations of genetics
  • Prospective studies of natural history
• Aging
• Younger, earlier disease
  • Study clinical variability (intra- and inter-familial)
  • Modifier genes
  • Environmental influences
• Further develop mouse model
  • Better characterization of mouse models
  • More robust and penetrant phenotype
  • Standardizing imaging
  • Genetic modifiers
  • Environmental factors
  • Sex differences?
• Mechanistic (translational) research in humans
  • Corroborating mice, men, cells
  • Developing therapies
  • Study environmental effects
• Explore novel therapies
  • Genomics and proteomics
  • Assay / model

What are the current major obstacles to his area of research?

• Complexity of pathophysiology
• Barriers to internal collaboration
  • Geographics
  • Academic competition
  • Variability in clinical care
  • Expertise/credentials for big clinical/epi research grants

What are the best ways to advance this area of research?

• Internal Collaboration
  • Databases
  • Infrastructure
  • Therapeutic trials
  • Tissue bank
    • Pathology
    • Tissues / blood
  • Big grant expertise and funding