ABSTRACT
The goal of this K08 Mentored Clinical Scientist Research Career Development Award application is to
provide the candidate with advanced skills needed to establish an independent research program investigating
the pathogenesis and therapeutics of monogenic high myopia (HM) and inherited retinal dystrophies (IRDs).
Our overall hypothesis is that increased TGFß signaling drives HM progression and structural changes
in the posterior segment indicative of pathological myopia (PM) in Marfan syndrome (MFS) and Rbp3-mediated
retinitis pigmentosa (RP). To test this hypothesis, the specific aims are to: 1) Determine the extent that Smad2/3
activation contributes to myopia progression, PM changes and retinal degeneration in MFS and Rbp3-/- mice; 2)
Define a role for TGFß-dependent MAPK activation in myopia progression, PM changes and retinal degeneration
in MFS and Rbp3-/- mice. This is based on an extensive review of the literature and our high-quality preliminary
data demonstrating that: 1) MFS mice have significantly greater axial length (AL) and -9D myopic shift compared
to WT littermates; 2) MFS mouse eyes show increased Smad2/3 and MAPK (Erk1/2, Jnk1/2, p38) activation in
the ciliary body and retina; 3) AL and myopic shift are reduced in MFS mice after Erk inhibition; 4) Smad3-/- mice
display shorter AL and a prominent hyperopic shift compared to WT littermates. These data indicate that TGFß
downstream pathways represent novel therapeutic targets for myopia and/or PM in MFS. Prior studies illustrated
that loss-of-function mutations in RBP3 cause autosomal recessive RP with HM (-12 to -17D) in humans, while
Rbp3-/- mice show markedly increased AL and myopic shift, as well as in-vivo and ex-vivo evidence of progressive
retinal degeneration. This offers an opportunity to evaluate a role for TGFß signaling in this etiologically-distinct
form of monogenic myopia, with the goal of identifying and targeting common drivers of disease progression.
The candidate is proposing a comprehensive training plan, combining formal coursework, meetings,
seminars and workshops overseen by his diverse, experienced mentorship team. His specific training goals
include to: 1) Refine his knowledge of in-vivo phenotyping of myopia and PM in mice, encompassing mouse eye
biometry, autorefraction, fundus photography and optical coherence tomography (OCT); 2) Develop skills in in-
vivo phenotyping of IRDs and their complications in mice, including ERG, OCT, and optomotor response (OMR);
3) Enhance his skills in ex-vivo histopathological and biochemical analysis of mouse myopia and IRD models,
including PM changes (e.g. retinal detachment, retinoschisis, posterior staphyloma) and retinal degeneration
(e.g. retinal thinning, photoreceptor loss); 4) Acquire management skills to build a successful independent
laboratory; 5) Develop leadership skills in collaborative research; 6) Refine his communication and writing skills
to successfully apply for R01 funding; 7) Continue training in responsible conduct of research. His training plan
will be executed in coordination with the research activities described above. Results from this proposal will be
used to develop a future R01 research plan that will facilitate the candidate’s transition to independent research.