Project Team: Diana Mitchell (PI), Ousseini Isaaka

Start Date: August 1, 2018

For the 19 genes without significant similarity to genes in humans, the following analyses will be performed in order to identify their putative functions:

1. identify conserved proteins or protein domains
2. predict protein localization
3. search for functional domains
4. predict cellular and functional pathways
5. synteny analysis for hypothetical proteins.

The team will identify suitable published RNA-seq datasets for zebrafish macrophages to probe for the presence / absence of these nonorthologous transcripts in other macrophage-mediated immune response.

After identifying conserved proteins or protein domains, we will go on to look for species that are known to have regenerative capacity.

Project Team: Craig Miller (PI), Aniruddha Belsare, JT Van Leuven

Start Date: June 2018

Context

Rabies kills an estimated 59,000 people every year. Most of these deaths are from the poorest sectors of society in low-­ and middle-­income countries, where dogs are the principal reservoir of rabies [1]. There are two ways to limit human rabies deaths: delivering timely post-­exposure prophylaxis and interrupting the transmission of rabies virus in dogs, the reservoir host. The advantage of interrupting transmission is that it addresses the source of the problem and provides enormous, long-­term public health and economic benefits. The World Health Organization (WHO) has set the goal of zero human deaths from dog-­mediated rabies by 2030. The proposed mechanism for accomplishing this is through vaccinating at high enough coverage (≥70%) to achieve herd immunity.

With more than 20,000 human deaths each year due to dog-­transmitted rabies, India has the highest disease burden [2, 3]. Furthermore, India also has the largest free-­ranging dog population in the world (~59 million) [4]. Achieving and sustaining high vaccination coverage across large geographic scale is a daunting challenge due to high population turnover rates, reliance on community participation to access dogs, cost, and lack of political will [5]. At present, rabies and dog population control programs in India are limited to a few urban centers. Ironically, most dog-­mediated human rabies deaths occur in rural areas of India [6].

Overarching Goal

The objective of this research is to find focused, efficient strategies for interrupting dog to dog transmission of rabies virus in resource-­limited settings. This will make a major contribution to eliminating dog-­mediated human rabies deaths in India and beyond.

Central Hypothesis

Our scientific hypothesis is that rabies arrives recurrently in rural dog populations through stepping-­stone dispersal originating in urban populations where the disease is endemic (Figure 1). Because dog population size is large in urban areas and small in rural villages, we also hypothesize that stochasticity is important in persistence (or lack thereof).

References

[1] Cleaveland S, Kaare M, Knobel D, Laurenson MK. Canine vaccination-­Providing broader benefits for disease control. Vet Microbiol. 2006;;117: 43–50.
[2] Burki T. The global fight against rabies. Lancet. 2008;;372: 1135–1136.
[3] Sudarshan MK, Madhusudana SN, Mahendra BJ, Rao NSN, Ashwath Narayana DH, Abdul Rahman S, et al. Assessing the burden of human rabies in India: results of a national multi-­center epidemiological survey. Int J Infect Dis. 2007;;11: 29–35.
[4] Gompper ME. The dog-­human-­wildlife interface: assessing the scope of the problem. In: Gompper ME, editor. Free-­Ranging Dogs and Wildlife Conservation. New York, USA: Oxford University Press;; 2014. pp. 9–54.
[5] Arechiga Ceballos N, Karunaratna D, Aguilar Setien A. Control of canine rabies in developing countries: key features and animal welfare implications. Rev Sci Tech l’OIE. 2014;;33: 311–321. doi:10.20506/rst.33.1.2278
[6] Suraweera W, Morris SK, Kumar R, Warrell DA, Warrell MJ, Jha P. Deaths from Symptomatically Identifiable Furious Rabies in India: A Nationally Representative Mortality Survey. PLoS Negl Trop Dis. 2012;;6. doi:10.1371/journal.pntd.0001847

Project Team: Paul Rowley (PI), Jagdish Patel

Start Date: April 1, 2018

This Modeling Access Grant (MAG) is to:

• build homology models for four toxin sequences based upon the KP4 toxin (~150 amino acid residues) crystal structure,
• run one micro second long molecular dynamics simulations of four homology models and KP4 toxin, and
• analyze simulations.

Project Directors: Kyle Harrington, Nathan Schiele

Project Team: Leo Epstein, Sophia Theodossiou, Aniruddha Belsare

Tendons are collagen-rich musculoskeletal tissues that transfer mechanical forces from muscle to bone to allow for normal human movements, such as locomotion. Unfortunately, tendon injuries are frequent, treatment options are limited, and the mechanical function of tendon rarely returns to pre-injury levels.

Recent efforts to develop engineered tendon replacements and improve tendon healing have focused on using mesenchymal stem cells (MSCs). However, these engineered tendon tissues have yet to match the structure and mechanical function of native tendons. Thus, there is a critical need to identify the mechanisms that direct tenogenesis (differentiation toward tendon) and tendon formation by MSCs before effective regeneration tendon approaches can be developed.

The team’s long-term goal and innovative approach is to advance tendon healing by identifying developmentally guided mechanisms that regulate tenogenesis in MSCs for use in engineered tissues and regenerative medicine.

In order to determine what role the cell network plays in regulating MSCs to form tendon, 2 computational models will be explored:

• an image-based model at the single cell scale, and
• a cell-cell network model.