# Dissecting the role of soluble a-Klotho in cardiovascular aging

> **NIH NIH K23** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $155,678

## Abstract

PROJECT SUMMARY/ABSTRACT
The proposed career development award will foster and promote the candidate's training and evolution toward
independent investigator. Candidate: Dr. Kenneth Lim is a clinical-translational investigator at the Division of
Nephrology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS). The proposed study
integrates patient-oriented research, cardiopulmonary exercise testing (CPET) technology, proteomics and
computational biology embedded in a rigorous training plan. Mentorship: Dr. Ravi Thadhani is the Chief of
Nephrology at the MGH, Professor of Medicine at HMS and Executive Director of Clinical Trials at Partners
Healthcare. He will serve as the primary mentor in conjunction with a multidisciplinary team of expert
collaborators. Research: Age-associated changes of the cardiovascular system and its complications are the
leading cause of death in patients with chronic kidney disease (CKD). Despite this, there are currently no direct
therapies available to treat this condition today. Klotho is a protein present in circulation that exerts highly
pleiotropic aging suppressive effects. Animal studies have demonstrated promising therapeutic properties of
Klotho that could be used for the treatment of cardiovascular disease in CKD. However, several fundamental
problems must first be overcome before future human interventional studies can proceed: Firstly, published
studies examining circulating Klotho with cardiovascular outcomes to-date have focused mainly on
morphological alterations, while clear evidence has shown that aging is tightly associated with reduced
cardiovascular functional reserve. Secondly, the precise levels of the various circulating isoforms of Klotho and
the nature of their specific roles in cardiovascular health are still undefined. Additionally, clinical studies to-date
assessing circulating Klotho are limited by the lack of a reliable Klotho assay. The overall aim of the proposed
study is therefore to bridge a critical gap in our understanding of the role of circulating Klotho in the regulation
of the cardiovascular aging response in CKD. We hypothesize that circulating Klotho deficiency is a major
determinant of premature cardiovascular aging in CKD.
In specific aim 1, we will characterize the relationship of the various Klotho isoforms with cardiovascular
structure and functional reserve using state-of-the-art CPET technology. We will define levels of circulating
Klotho isoforms in health and advanced CKD (cross-sectional), and after kidney transplantation (prospectively).
Circulating Klotho isoform levels will be assessed using an established immunoprecipitation and western
blotting method. Additionally, the proposed study will provide a robust platform to validate and confirm a new
targeted proteomics assay that we have developed for the precision assessment of circulating Klotho isoforms.
In specific aim 2, we will conduct a cross-section study to characterize the relationship of cir...

## Key facts

- **NIH application ID:** 10155477
- **Project number:** 5K23DK115683-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Kenneth Lim
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,678
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155477

## Citation

> US National Institutes of Health, RePORTER application 10155477, Dissecting the role of soluble a-Klotho in cardiovascular aging (5K23DK115683-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10155477. Licensed CC0.

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