Dataset Information

ID1 and ID3 are Negative Regulators of TGFβ2-Induced Ocular Hypertension and Compromised Aqueous Humor Outflow Facility in Mice.

ABSTRACT:

Purpose

In POAG, elevated IOP remains the major risk factor in irreversible vision loss. Increased TGFβ2 expression in POAG aqueous humor and in the trabecular meshwork (TM) amplifies extracellular matrix (ECM) deposition and reduces ECM turnover in the TM, leading to a decreased aqueous humor (AH) outflow facility and increased IOP. Inhibitor of DNA binding proteins (ID1 and ID3) inhibit TGFβ2-induced fibronectin and PAI-1 production in TM cells. We examined the effects of ID1 and ID3 gene expression on TGFβ2-induced ocular hypertension and decreased AH outflow facility in living mouse eyes.

Methods

IOP and AH outflow facility changes were determined using a mouse model of Ad5-hTGFβ2C226S/C288S-induced ocular hypertension. The physiological function of ID1 and ID3 genes were evaluated using Ad5 viral vectors to enhance or knockdown ID1/ID3 gene expression in the TM of BALB/cJ mice. IOP was measured in conscious mice using a Tonolab impact tonometer. AH outflow facilities were determined by constant flow infusion in live mice.

Results

Over-expressing ID1 and ID3 significantly blocked TGFβ2-induced ocular hypertension (P < 0.0001). Although AH outflow facility was significantly decreased in TGFβ2-transduced eyes (P < 0.04), normal outflow facility was preserved in eyes injected concurrently with ID1 or ID3 along with TGFβ2. Knockdown of ID1 or ID3 expression exacerbated TGFβ2-induced ocular hypertension.

Conclusions

Increased expression of ID1 and ID3 suppressed both TGFβ2-elevated IOP and decreased AH outflow facility. ID1 and/or ID3 proteins thus may show promise as future candidates as IOP-lowering targets in POAG.

SUBMITTER: Mody AA

PROVIDER: S-EPMC8107646 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Herein partially summarizes one scientist-clinician's wanderings through the jungles of primate aqueous humor outflow over the past ~45 years. Totally removing the iris has no effect on outflow facility or its response to pilocarpine, whereas disinserting the ciliary muscle (CM) from the scleral spur/trabecular meshwork (TM) completely abolishes pilocarpine's effect. Epinephrine increases facility in CM disinserted eyes. Cytochalasins and latrunculins increase outflow facility, subthreshold doses of cytochalasins and epinephrine given together increase facility, and phalloidin, which has no effect on facility, partially blocks the effect of both cytochalasins and epinephrine. H-7, ML7, Y27632 and nitric oxide - donating compounds all increase facility, consistent with a mechanosensitive TM/SC. Adenosine A1 agonists increase and angiotensin II decrease facility. OCT and optical imaging techniques now permit visualization and digital recording of the distal outflow pathways in real time. Prostaglandin (PG) F2α analogues increase the synthesis and release of matrix metalloproteinases by the CM cells, causing remodeling and thinning of the interbundle extracellular matrix (ECM), thereby increasing uveoscleral outflow and reducing IOP. Combination molecules (one molecule, two or more effects) and fixed combination products (two molecules in one bottle) simplify drug regimens for patients. Gene and stem cell therapies to enhance aqueous outflow have been successful in laboratory models and may fill an unmet need in terms of patient compliance, taking the patient out of the delivery system. Functional transfer of genes inhibiting the rho cascade or decoupling actin from myosin increase facility, while genes preferentially expressed in the glaucomatous TM decrease facility. In live NHP, reporter genes are expressed for 2+ years in the TM after a single intracameral injection, with no adverse reaction. However, except for one recent report, injection of facility-effective genes in monkey organ cultured anterior segments (MOCAS) have no effect in live NHP. While intracameral injection of an FIV. BOVPGFS-myc.GFP PGF synthase vector construct reproducibly induces an ~2 mmHg reduction in IOP, the effect is much less than that of topical PGF2⍺ analogue eyedrops, and dissipates after 5 months. The turnoff mechanism has yet to be defeated, although proteasome inhibition enhances reporter gene expression in MOCAS. Intracanalicular injection might minimize off-target effects that activate turn-off mechanisms. An AD-P21 vector injected sub-tenon is effective in 'right-timing' wound healing after trabeculectomy in live laser-induced glaucomatous monkeys. In human (H)OCAS, depletion of TM cells by saponification eliminates the aqueous flow response to pressure elevation, which can be restored by either cultured TM cells or by IPSC-derived TM cells. There were many other steps along the way, but much was accomplished, biologically and therapeutically over the past half century of research and development focused on one very small but complex ocular apparatus. I am deeply grateful for this award, named for a giant in our field that none of us can live up to.