Integrative Molecular Genetics Laboratory

Dr. Ludlow is an Assistant Professor and is the director of the Integrative Molecular Genetics laboratory in the School of Kinesiology. In this laboratory, we study how humans change when they age and/or become diseased using a combination of cell biology, biochemistry, genetics, molecular biology, and physiology. Current research projects are focused on three major areas:

  1. alternative splicing regulation in aging and cancer;
  2. telomere length induced changes in chromatin and gene expression;
  3. exercise-induced adaptations that prevent age-related diseases.

The ultimate goal is to find actionable molecules or design lifestyle interventions (diet and exercise) that prevent age-related diseases such as cancer and cardiometabolic diseases.

IMGL Ludlow lab photo

Contact

Address: 
CCRB 1211
401 Washtenaw Ave.
Ann Arbor, MI 48109-2214
(734) 763-4708
(734) 936-1925

Director

Projects

Regulation and manipulation of hTERT/telomerase splicing in cancer cells

The enzyme telomerase is expressed in most cancer types, making telomerase a highly attractive potential therapeutic target for producing stable cancer remissions. Furthermore, telomerase is a hallmark of cancer cells and understanding how telomerase is regulated may point out other specific features of cancers cells that can be targeted for therapeutic purposes (i.e., finding the Achilles’ heal of cancer or cancer cell dependencies). We hypothesize that shifting the splicing of hTERT mRNAs from activity producing transcripts to transcripts that do not generate active telomerase may shorten telomeres in cancer cells and produce long term stable cancer remissions. To this end we have identified splicing factors and cis elements that cancer cells utilize to promote the production of full length TERT mRNAs. Further, research will utilize this knowledge to block the binding of these proteins to their cis elements to reduce full length TERT, reduce telomerase activity and shorten telomeres. By developing a thorough understanding of the molecular regulation of TERT splicing we may be able to identify novel targets for therapeutic purposes. The ultimate goal of this project would be to develop therapies for cancer (reducing telomerase). Currently this project is funded by a National Cancer Institute Pathway to Independence award (K99/R00). We are in the first of three years of the R00 phase of funding.

Cancer, telomeres and lifestyle (diet and exercise): Is there a connection?

Description: Telomere length shortens with age. Telomere shortening over time or progressive telomere shortening leads to senescence, apoptosis, and potentially oncogenic transformation of cells, which in turn shortens the health span and lifespan of individuals. Certain lifestyle factors can alter the rate of telomere shortening, for instance, the rate of telomere shortening is slowed down by maintaining a moderate level of physical activity. Diseases of inactivity such as insulin resistance, chronic inflammation, and altered endocrine signaling may increase the rate of telomere shortening and increase the risk of cancer. Thus, this project broadly aims to understand the connections between lifestyle factors (diet and exercise), the regulation of telomere length, and how this alters the risk for certain cancers. Initial studies will focus on the mechanisms of how exercise and diet influence telomerase activity and telomere length regulating proteins, particularly focusing on the signaling mechanisms that result in enhanced telomere protection and maintenance (DNA repair, fidelity of DNA replication, etc.) and how this affords genome stability and reduced cancer risk. In particular we will focus on how somatotrophic signaling results in altered chromatin, epigenetics, transcriptional factor recruitment, and splicing of TERT/human TERT, following diet and exercise interventions to slow the rate of telomere shortening. To perform this research, we will use a combination of human participants, rodent models and human/mouse tissue culture models. The ultimate goal of this research will be to define the molecules that are triggered by healthy lifestyle choices that result in enhanced genome stability (i.e., telomere maintenance) and develop therapeutics to target these molecules to treat diseases of short telomeres and reduce the risk of certain cancer types.

Telomere length induced changes in gene expression: mechanistic role in metabolism and aging

Description: Telomere length is involved in the regulation of gene expression, through telomere position effects (TPE). Traditional TPE is a phenomenon where when telomeres are long, they are heterochromatic and thus genes nearby are silenced (not expressed), and when telomeres shorten the spreading of heterochromatin results in the expression (aberrant in some cases) of genes near telomeres. In addition, telomeres form chromatin loops that are dependent on the length of telomeres and make contacts with enhancer and repressor regions leading to altered genes expression in a non-linear fashion. Since many human genes including microRNAs, splicing factors, and genes in that regulate metabolism, are within 10Mb of chromosome ends, it is likely that telomere position effects over long distances (TPE-OLD) plays a role in aging and disease risk. Initial studies will focus on how splicing factors/RNA binding proteins and non-coding RNAs are regulated by telomere length and in turn how the mis-expression of these factors/RNAs alters metabolism of various cell types, such as, immune cells, mesenchymal stem cells, muscle cells and epithelial cells. The major questions we would be trying to answer are how telomere length plays a role in disease progression processes such as immune-senescence, type II diabetes, and cancer progression. Ultimately, we would try to reverse the effects of short telomeres on gene expression of these important splicing factors/non-coding RNAs by developing interventions to maintain or slow the rate of telomere shortening by enhancing telomerase biogenesis via increased exercise, healthy diet, or therapeutics.